O-aryl, O-alkyl, O-alkenyl and O-alkynyl-macrolides having immunosuppressive activity

ABSTRACT

Substituted compounds of the FK-506 Type. These compounds are useful for the same or essentially the same purposes as FK-506 and are applied in the same or a similar manner. These compounds are immunosuppressants and useful for the treatment of autoimmune diseases, infectious diseases and/or the prevention of rejection of foreign organ transplants. Still other uses are described in the disclosure.

This application is a 371 of PCT/US 94/11114, filed 30 Sept. 1994 whichclaims priority of U.S. application Ser. No. 08/132,072, filed 4 Oct.1993.

SUMMARY OF THE INVENTION

The present invention is related to O-aryl, O-alkyl, O-alkenyl andO-alkynylmacrolides which are useful in a mammalian subject for thetreatment of autoimmune diseases (such as juvenile-onset or recent-onsetdiabetes mellitus, multiple sclerosis, and rheumatoid arthritis, liverdisease, posterior uveitis, allergic encephalomyelitis, andglomerulonephritis), immunodepression, infectious diseases and/or theprevention of rejection of foreign organ transplants, (e.g. bone marrow,kidney, liver, heart, skin, small-bowel, and pancreatic islet-celltransplants, including xeno transplants), the topical treatment ofinflammatory and hyperproliferative skin diseases and cutaneousmanifestations of immunologically-mediated illnesses (such as:psoriasis, atopical dermatitis, contact dermatitis and furthereczematous dermatitises, seborrhoeic dermatitis, Lichen planus,Pemphigus, bullous Pemphigoid, Epidermolysis bullosa, urticaria,angioedemas, vasculitides, erythemas, cutaneous eosinophilias, Lupuserythematosus or Alopecia areata), male pattern alopecia, alopeciasenilis, reversible obstructive airways disease, particularly asthma,inflammation of mucosa and blood vessels, cytomegalovirus infection,multidrug resistance, idiopathic thromboytopenic purpura, Behcet'ssyndrome, conjunctivitis, Crohn's disease, Mooren's ulcer, uveitis,servere intraocular inflammation and/or hepatic injury associated withischemia. The present compounds are further useful in combination with a5α-reductase inhibitor, a cyclosporin, a potassium channel opener or aphospholipid in a mammalian host for the treatment of baldness,especially male pattern alopecia, female pattern alopecia, alopeciasenilis, or Alopecia areata. In addition, some of the compounds of thisinvention may have antagonistic properties and so have utility in thereversal of immunosuppressive activity and/or diminishing the toxicityof other immunosuppressive agents.

More particularly, this invention relates to compounds of the generalstructural Formula I: ##STR1## wherein R¹, R², R³, R⁴, R⁵, W and n arehereinafter defined.

This invention also relates to pharmaceutical compositions containingthe compounds, and to a method of use of the present compounds and otheragents for the treatment and prevention of certain afflictions, diseasesand illnesses.

BRIEF DESCRIPTION OF DISCLOSURES IN THE ART

Fujisawa United States, European and Japanese patents and applications(U.S. Pat. No. 4,894,366, issued Jan. 16, 1990, EPO Publication No.0,184,162 and PBJ Disclosure 63-17884) and publications (J. Am. Chem.Soc., 1987, 109, 5031 and J. Antibiotics 1987, 40, 1249) disclose17-allyl-1,14-dihydroxy-12-2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (FR-900506) (FK-506)(L-679,934), 17-ethyl-1,14-dihydroxy-12-2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methyl-vinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-22.3.1.0⁴,9!-octacos-18-ene-2,3,10,16-tetraone (FR-900520) and related compoundswhich are the starting materials for the preparation of the compoundsdescribed. The synthetic preparation of the aforementioned startingmaterial (FR-900506) has been reported (J. Am. Chem. Soc., 1989, 111,1157). A Sandoz U.S. patent (U.S. Pat. No. 5,011,844) and Europeanpatent application (EPO Publication No. 0,356,399) disclosestereoisomers of FR-900506 and derivatives at the 17-position. FisonsEuropean and WIPO patent applications (EPO Publication No. 0,323,042 andPCT Publication No. WO89/05304) disclose various derivatives ofFR-900506, FR-900520 and related compounds. A Sandoz European patentapplication (EPO Publication No. 0,437,680) discloses chloro, bromo,iodo and azido derivatives of FR-900506, FR-900520 and relatedcompounds. A Merck European patent application (EPO Publication No.0,428,365) discloses various amino derivatives of FR-900506, FR-900520and related compounds. A Fujisawa UK patent application (UK PublicationNo. GB 2,245,891A) discloses various aryl(lower alkyl) and heteroarylderivatives of FR-900506, FR-900520 and related compounds. Merck WIPOpatent applications (PCT Publication Nos. WO 93/05058 & WO 93/05059)disclose various heteroaryl derivatives of FR-900506, FR-900520 andrelated compounds.

Fujisawa United States patents (U.S. Pat. No. 4,929,611, issued May 29,1990 and U.S. Pat. No. 4,956,352, issued Sept. 11, 1990) disclose theuse of FK-506-type compounds in treating resistance to transplantation.A Sandoz European patent application (EPO Publication No. 0,315,978)discloses the use of FR-900506 and related compounds in the topicaltreatment of inflammatory and hyper-proliferative skin diseases and ofcutaneous manifestations of immunologically-mediated illness. A FisonsWorld patent application (PCT Publication WO 90/14826) discloses the useof FR-900506 and related compounds in the treatment of reversibleobstructive airways disease, particularly asthma. A Fujisawa Europeanpatent application (EPO Publication No. 0,423,714) discloses the use ofFK-506 and derivatives as hair revitalizing agents. Various studies havesuggested the efficacy of FK-506 in the treatment of a number ofailments, including rheumatoid arthritis (C. Arita, et al., Clincialexp. Immunol., 1990, 82, 456-461; N. Inamura, et al., Clin. Immunol.Immunopathol. 1988, 46, 82-90), recent-onset diabetes (N. Murase, etal., Diabetes, 1990, 39, 1584-86; N. Murase, et al., Lancet, 1990, 336,373-74), posterior uveitis (H. Kawashima, Invest. Ophthalmul. Vis. Sci.,1988, 29, 1265-71), hepatic injury associated with ischemia (M. Sakr, etal., Life Sci., 1990, 47, 687-91) allergic encephalomyelitis (K.Deguchi, et al., Brain Nerve, 1990, 42, 391-97), glomerulonephritis (J.McCauley, et al., Lancet, 1990, 335, 674), systemic lupus erythematosus(K. Takabayashi, et al., Clin. Immunol. Immunopathol., 1989, 51,110-117), multidrug resistance (M. Naito, et al., Cancer Chemother.Pharmacol., 1992, 29, 195-200), inflammation of mucosa and blood vessels(PCT Publication WO 91/17754), cytomegalovirus infection (UK PublicationGB 2,247,620A), and idiopathic thrombocytopenic purpura and Basedow'sdisease (PCT Publication WO 91/19495).

BACKGROUND OF THE INVENTION

Immunoregulatory abnormalities have been shown to exist in a widevariety of "autoimmune" and chronic inflammatory diseases, includingsystemic lupus erythematosis, chronic rheumatoid arthritis, type 1diabetes mellitus, type 2 adult onset diabetes, inflammatory boweldisease, biliary cirrhosis, uveitis, multiple sclerosis and otherdisorders such as Crohn's disease, ulcerative colitis, bullouspemphigoid, sarcoidosis, psoriasis, ichthyosis, and Gravesophthalmopathy. Although the underlying pathogenesis of each of theseconditions may be quite different, they have in common the appearance ofa variety of autoantibodies and self-reactive lymphocytes. Suchself-reactivity may be due, in part, to a loss of the homeostaticcontrols under which the normal immune system operates.

Similarly, following a bone-marrow or an organ transplantation, the hostlymphocytes recognize the foreign tissue antigens and begin to produceantibodies which lead to graft rejection.

One end result of an autoimmune or a rejection process is tissuedestruction caused by inflammatory cells and the mediators they release.Antiinflammatory agents such as NSAID's and corticosteroids actprincipally by blocking the effect or secretion of these mediators butdo nothing to modify the immunologic basis of the disease. On the otherhand, cytotoxic agents such as cyclophosphamide, act in such anonspecific fashion that both the normal and autoimmune responses areshut off. Indeed, patients treated with such nonspecificimmunosuppressive agents are as likely to succumb from infection as theyare from their autoimmune disease.

Cyclosporin A which was approved by the US FDA in 1983 is currently theleading drug used to prevent rejection of transplanted organs. The drugacts by inhibiting the body's immune system from mobilizing its vastarsenal of natural protecting agents to reject the transplant's foreignprotein. Though cyclosporin A is effective in fighting transplantrejection, it is nephrotoxic and is known to cause several undesirableside effects including kidney failure, abnormal liver function andgastrointestinal discomfort.

Newer, safer drugs exhibiting less side effects are constantly beingsearched for in the field.

The 23-membered tricyclo-macrolide immunosuppressant, tacrolimus,FR-900506, FK-506, ##STR2## (17-allyl-1,14-dihydroxy-12-2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-22.3.1.0⁴,9 !-octacos-18-ene-2,3,10,16-tetraone) and related compoundswhich were isolated and characterized by Tanaka, Kuroda, and co-workersat Fujisawa Pharmaceutical Co. in Japan, see J. Am. Chem. Soc., 1987,109, 5031, and U.S. Pat. No. 4,894,366, issued Jan. 16, 1990) have beenshown to possess exceptional immunosuppressive activity. Fujisawa UnitedStates patents (U.S. Pat. No. 4,929,611, issued May 29, 1990 and U.S.Pat. No. 4,956,352, issued Sep. 11, 1990) disclose the use ofFK-506-type compounds in treating resistance to transplantation. Inparticular, the compound FR-900506 has been reported to be 100 timesmore effective than cyclosporin in the suppression of in vitro immunesystems (J. Antibiotics, 1987, 40, 1256). In addition, these compoundsare reputed to possess topical activity in the treatment of inflammatoryand hyperproliferative skin diseases and cutaneous manifestations ofimmunologically-mediated illnesses (EPO Pub. No. 0,315,978).

The compound FK-506 and related compounds further have been suggested tobe useful in the treatment of obstructive airways disease, particularlyasthma (PCT Publication WO 90/14826), male pattern alopecia or alopeciasenilis (EPO Publication No. 0,423,714), rheumatoid arthritis (C. Arita,et al., Clincial exp. Immunol., 1990, 82, 456-461; N. Inamura, et al.,Clin. Immunol. Immunopathol., 1988, 46, 82-90), recent-onset diabetes(N. Murase, et al., Diabetes, 1990, 39, 1584-86; N. Murase, et al.,Lancet, 1990, 336, 373-74), posterior uveitis (H. Kawashima, Invest.Ophthalmol. Vis. Sci., 1988, 29, 1265-71), hepatic injury associatedwith ischemia (M. Sakr, et al., Life Sci., 1990, 47,687-91) allergicencephalomyelitis (K. Deguchi, et al., Brain Nerve, 1990, 42, 391-97),glomerulonephritis (J. McCauley, et al., Lancet, 1990, 335, 674),systemic lupus erythematosus (K. Takabayashi, et al., Clin. Immunol.Immunopathol., 1989, 51, 110-117) multidrug resistance (M. Naito, etal., Cancer Chemother. Pharmacol., 1992, 29, 195-200), inflammation ofmucosa and blood vessels (PCT Publication WO 92/17754), cytomegalovirusinfection (UK Publication GB 2,247,620A), and idiopathicthrombocytopenic purpura and Basedow's disease (PCT Publication WO91/19495).

Baldness or alopecia, in addition to male pattern alopecia, femalepattern alopecia, and alopecia senilis, includes Alopecia areta, andfurther, diseases accompanied by basic skin lesions such as cicatrix orinfectious tumors, or accompanied by systemic disorders, for examples,an internal secretion abnormality or nutritional disorder.

In regard to Alopecia areata, it is considered that an autoimmunephenomenon participates therein, and therefore, the administration of asubstance having an immunosuppressive action can have therapeuticaleffect on Alopecia areata.

The causes of human pattern alopecia (also called "androgenic alopecia")and alopecia senilis are considered to be: an activation of malehormones at organs such as hair roots and the sebum gland; a lowering inthe amount of blood reaching the hair follicles; a scalp abnormalitycaused by an excessive secretion of sebum, a formation or peroxides, ora propagation of bacteria; genetic; causes; and aging.

The compound minoxidil(6-amino-1,2-dihydro-1-hydroxy-2-imino-4-piperidinopyrimidine) wasapproved by the FDA for the treatment of male pattern baldness in August1988. Minoxidil was also approved by the FDA for the treatment of femaleandrogenetic alopecia on Aug. 13, 1991. The preparation of minoxidil isdescribed in U.S. Pat. Nos. 3,382,247, 3,644,364 and 4,098,791. UpjohnUnited States Patents (U.S. Pat. Nos. 4,139,619 and 4,596,812) disclosesthe use of minoxidil in the topical treatment of human baldness.Similarly, an Upjohn United States Patent (U.S. Pat. No. 5,026,691)discloses the use of minoxidil and an antiinflammatory agent for thetreatment of patterned male and female alopecia. Japanese patent Kokai61-260010 states that topical minoxidil formulations containing otherspecified agents may be prepared. An Upjohn WIPO patent application (PCTPublication No. WO 92/09259) discloses a method and composition forpromoting hair growth in mammals comprising the administration of apotassium channel opener and an androgen receptor blocker. A Universityof Miami WIPO patent application (PCT Publication No. WO 92/12703)discloser a method of stimulating hair growth comprising the topicalapplication of a phospholipid.

Merck United States Pat. No. 4,760,071 discloses the 5α-reductaseinhibitor 17β-(N-tert-butylcarbamoyl)-4-aza-5α-androst-1-en-3-one.Harris, et al., (Proc. Natl. Acad. Sci. USA, 89, 10787-10791 (November1992)) and Melin, et al. (J. Steroid Biochem, Molec. Biol., 44(2),121-131 (1993)) disclose the use of scalp-selective 5α-reductaseinhibitors in the treatment of male pattern baldness, acne andhirsutism.

DETAILED DESCRIPTION OF THE INVENTION

A. Scope of the Invention

The novel compound of this invention has structural Formula I: ##STR3##or a pharmaceutically acceptable salt thereof, wherein: R¹ and R² areindependently selected from:

(1) hydrogen;

(2) phenyl;

(3) substituted phenyl in which the substituents are X, Y and Z;

(4) 1- or 2-naphthyl;

(5) substituted 1- or 2-naphthyl in which the substituents are X, Y andZ;

(6) biphenyl;

(7) substituted biphenyl in which the substituents are X, Y and Z;

(8) C₁₋₁₀ alkyl;

(9) substituted C₁₋₁₀ alkyl in which one or more substituent(s) is(are)selected from:

(a) hydroxy,

(b) oxo,

(c) C₁₋₆ alkoxy,

(d) phenyl-C₁₋₃ alkoxy,

(e) substituted phenyl-C₁₋₃ alkoxy, in which the substituents on phenylare X, Y and Z,

(f) --OCO--C₁₋₆ alkyl,

(g) --NR⁶ R⁷, wherein R⁶ and R⁷ are independently selected from:

(i) hydrogen,

(ii) C₁₋₁₀ alkyl unsubstituted or substituted with one or more of thesubstituent(s) selected from:

(a') phenyl, which is unsubstituted or substituted with X, Y and Z,

(b') --OH,

(c') C₁₋₆ alkoxy,

(d') --CO₂ H,

(e') --CO₂ --C₁₋₆ alkyl,

(f') --C₃₋₇ cycloalkyl, and

(g') --OR¹¹,

(iii) C₃₋₁₀ alkenyl unsubstituted or substituted with one or more of thesubstituent(s) selected from:

(a') phenyl, which is unsubstituted or substituted with X, Y and Z,

(b') --OH,

(c') C₁₋₆ alkoxy,

(d') --CO₂ H,

(e') --CO₂ --C₁₋₆ alkyl,

(f') --C₃₋₇ cycloalkyl, and

(g') --OR¹¹,

(iv) or where R⁶ and R⁷ and the N to which they are attached can form anunsubstituted or substituted 3-7-membered saturated heterocyclic ringwhich can include one or two additional heteroatoms independentlyselected from the group consisting of O, S(O)_(p), NR¹⁴, wherein R¹⁴ ishydrogen or C₁₋₆ alkyl unsubstituted or substituted by phenyl, and p is0, 1 or 2, the ting being selected from the group consisting of:aziridine, morpholine, thiomorpholine, thiomorpholine-oxide,thiomorpholine-dioxide, piperidine, pyrrolidine, and piperazine,

(h) --NR⁶ CO--C₁₋₆ alkyl-R⁷, wherein R⁶ is as defined above,

(i) --NR⁶ CO₂ --C₁₋₆ alkyl-R⁷,

(j) --NR⁶ CONR⁶ R⁷,

(k) --OCONR⁶ R⁷,

(l) --COOR⁶,

(m) --CHO,

(n) phenyl,

(o) substituted phenyl in which the substituents are X, Y and Z,

(p) phenyloxy,

(q) substituted phenyloxy in which the substituents are X, Y and Z,

(r) 1- or 2-naphthyl,

(s) substituted 1- or 2-naphthyl in which the substituents are X, Y andZ,

(t) biphenyl,

(u) substituted biphenyl in which the substituents are X, Y and Z;

(v) --OR¹¹, and

(w) --S(O)_(p) --C₁₋₆ alkyl;

(10) C₃₋₁₀ alkenyl;

(11) substituted C₃₋₁₀ alkenyl in which one or more substituent(s)is(are) selected from:

(a) hydroxy,

(b) oxo,

(c) C₁₋₆ alkoxy,

(d) phenyl-C₁₋₃ alkoxy,

(e) substituted phenyl-C₁₋₃ alkoxy, in which the substituents on phenylare X, Y and Z,

(f) --OCO--C₁₋₆ alkyl,

(g) --NR⁶ R⁷, wherein R⁶ and R⁷ are as defined above,

(h) --NR⁶ CO--C₁₋₆ alkyl, wherein R⁶ is as defined above,

(i) --COOR⁶, wherein R⁶ is as defined above,

(j) --CHO,

(k) phenyl,

(l) substituted phenyl in which the substituents are X, Y and Z,

(m) 1- or 2-naphthyl,

(n) substituted 1- or 2-naphthyl in which the substituents are X, Y andZ,

(o) biphenyl,

(p) substituted biphenyl in which the substituents are X, Y and Z,

(q) --OR¹¹, and

(r) --S(O)_(p) --C₁₋₆ alkyl;

(12) C₃₋₁₀ alkynyl;

(13) substituted C₃₋₁₀ alkynyl in which one or more substituent(s)is(are) selected from:

(a) hydroxy,

oxo,

(c) C₁₋₆ alkoxy,

(d) phenyl-C₁₋₃ alkoxy,

(e) substituted phenyl-C₁₋₃ alkoxy, in which the substituents on phenylare X, Y and Z,

(f) --OCO--C₁₋₆ alkyl,

(g) --NR⁶ R⁷, wherein R⁶ and R⁷ are as defined above,

(h) --NR⁶ CO--C₁₋₆ alkyl, wherein R⁶ is as defined above,

(i) --COOR⁶, wherein R⁶ is as defined above,

(j) --CHO,

(k) phenyl,

(l) substituted phenyl in which the substituents are X, Y and Z,

(m) 1- or 2-naphthyl,

(n) substituted 1- or 2-naphthyl in which the substituents are X, Y andZ,

(o) biphenyl,

(p) substituted biphenyl in which the substituents are X, Y and Z, and

(q) --OR¹¹ ;

with the proviso that R¹ and R² are not simultaneously hydrogen, methylor combinations thereof;

R³ is hydrogen, hydroxy, --OR¹¹ or C₁₋₆ alkoxy;

R⁴ is hydrogen, or R³ and R⁴ taken together form a double bond;

R⁵ is methyl, ethyl, propyl or allyl;

R¹¹ is selected from:

(a) --PO(OH)O⁻ M⁺, wherein M⁺ is a positively charged inorganic ororganic counterion,

(b) --SO₃ ⁻ M⁺,

(c) --CO(CH₂)_(q) CO₂ ⁻ M⁺, wherein q is 1-3, and

(d) --CO--C₁₋₆ alkyl-NR⁶ R⁷, wherein R⁶ and R⁷ are as defined above andthe alkyl is unsubstituted or substituted with one or more substituentsselected from:

(i) hydroxy,

(ii) C₁₋₆ alkoxy,

(iii) --NR¹⁶ R¹⁷, wherein R¹⁶ and R¹⁷ are independently selected from:

(a') hydrogen, and

(b') C₁₋₆ alkyl,

(iv) --COOR⁶, wherein R⁶ is as defined above,

(v) phenyl,

(vi) substituted phenyl in which the substituents are X, Y and Z,

(vii) --SH, and

(viii) --S--C₁₋₆ alkyl;

W is O or (H, OH);

X, Y and Z independently are selected from:

(a) hydrogen,

(b) C₁₋₇ alkyl,

(c) C₂₋₆ alkenyl,

(d) halogen,

(e) --(CH₂)_(m) --NR⁶ R⁷, wherein R⁶ and R⁷ are as defined above, and mis 0 to 2,

(f) --CN,

(g) --CHO,

(h) --CF₃,

(i) --SR⁸, wherein R⁸ is hydrogen, C₁₋₆ alkyl, trifluoromethyl, orphenyl,

(j) --SOR⁸, wherein R⁸ is as defined above,

(k) --SO₂ R⁸, wherein R⁸ is as defined above,

(l) --CONR⁶ R⁷, wherein R⁶ and R⁷ are as defined above,

(m) R⁹ O(CH₂)_(m) -- wherein R⁹ is hydrogen, C₁₋₃ alkyl, hydroxy-C₂₋₃alkyl, trifluoromethyl, phenyl or naphthyl and m is as defined above,

(n) --CH(OR¹²)(OR¹³), wherein R¹² and R¹³ are C₁₋₃ alkyl or takentogether form an ethyl or propyl bridge,

(o) ##STR4## wherein R⁹ and m are as defined above, and (p) ##STR5##wherein R⁹ and m are as defined above, and (q) --OR¹¹ ; or any two ofadjacent X, Y and Z can be joined to form a ring having 5, 6 or 7 ringatoms, said ring atoms comprising 1 or 2 oxygen atoms, the remainingring atoms being carbon, selected from the group consisting of:dioxolanyl, dihydrofuranyl, dihydropyranyl, and dioxanyl; and

n is 1 or 2.

The compounds of the present invention have asymmetric centers and thisinvention includes all of the optical isomers and mixtures thereof.

In addition compounds with carbon-carbon double bonds may occur in Z-and E- forms with all isomeric forms of the compounds being included inthe present invention.

When any variable (e.g., alkyl, aryl, R⁶, R⁷, R⁸, R⁹, R¹⁰ R¹¹, etc.)occurs more than one time in any variable or in Formula I, itsdefinition on each occurrence is independent of its definition at everyother occurrence.

As used herein, the term "alkyl" includes those alkyl groups of adesignated number of carbon atoms of either a straight, branched, orcyclic configuration. Examples of "alkyl" include methyl, ethyl, propyl,isopropyl, butyl, sec-and tert-butyl, pentyl, hexyl, heptyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,norbornyl, and the like. "Alkoxy" represents an alkyl group of indicatednumber of carbon atoms attached through an oxygen bridge, such asmethoxy, ethoxy, propoxy, butoxy and pentoxy.

"Alkanoyl" is intended to include those alkylcarbonyl groups ofspecified number of carbon atoms, which are exemplified by formyl,acetyl, propanoyl and butyryl; "alkanoyloxy" is intended to includethose alkylcarbonyl groups of specified number of carbon atoms attachedthrough an oxygen bridge, which are exemplified by formyloxy, acetoxy,propionoyloxy, and butyryloxy. "Alkenyl" is intended to includehydrocarbon chains of a specified number of carbon atoms of either astraight- or branched-configuration and at least one unsaturation, whichmay occur at any point along the chain, such as ethenyl, propenyl,butenyl, pentenyl, dimethyl pentenyl, and the like, and includes E and Zforms, where applicable; and "arylalkyl" represents aryl groups asherein defined which are attached through a straight or branched chainalkyl group of from one to six carbon atoms, such as, for example,benzyl, phenethyl, 3,3-diphenylpropyl, and the like. "Halogen", as usedherein, means fluoro, chloro, bromo and iodo.

As will be understood by those skilled in the art, pharmaceuticallyacceptable salts include, but are not limited to salts with inorganicacids such as hydrochloride, sulfate, phosphate, diphosphate,hydrobromide, and nitrate or salts with an organic acid such as malate,maleate, fumarate, tartrate, succinate, citrate, acetate, lactate,methanesulfonate, p-toluenesulfonate or palmoate, salicylate andstearate. Similarly pharmaceutically acceptable cations include, but arenot limited to sodium, potassium, calcium, aluminum, lithium andammonium (especially ammonium salts with amines of the formula HNR⁶ R⁷).

One embodiment of the present invention encompasses the compounds ofFormula I wherein:

R¹ and R² are independently selected from:

(1) hydrogen;

(2) methyl;

(3) phenyl;

(4) substituted phenyl in which the substituents are X, Y and Z;

(5) 1- or 2-naphthyl;

(6) substituted 1- or 2-naphthyl in which the substituents are X, Y andZ;

(7) biphenyl; and

(8) substituted and biphenyl in which the substituents are X, Y and Z;

with the proviso that R¹ and R² are not simultaneously hydrogen, methylor combinations thereof;

R³ is hydrogen, hydroxy, or C₁₋₆ alkoxy;

R⁴ is hydrogen, or R³ and R⁴ taken together form a double bond;

R⁵ is methyl, ethyl, propyl or allyl;

R¹¹ is selected from:

(a) --PO(OH)O⁻ M⁺, wherein M⁺ is a positively charged inorganic ororganic counterion,

(b) --SO₃ ⁻ M⁺,

(c) --CO(CH₂)_(q) CO₂ ⁻ M⁺, wherein q is 1-3, and

(d) --CO--C₁₋₆ alkyl-NR⁶ R⁷, wherein R⁶ and R⁷ are as defined below andthe alkyl is unsubstituted or substituted with one or more substituentsselected from:

(i) hydroxy,

(ii) C₁₋₆ alkoxy,

(iii) --NR¹⁶ R¹⁷, wherein R¹⁶ and R¹⁷ are independently selected from:

(a') hydrogen, and

(b') C₁₋₆ alkyl,

(iv) --COOR⁶, wherein R⁶ is as defined below,

(v) phenyl,

(vi) substituted phenyl in which the substituents are X, Y and Z,

(vii) --SH, and

(viii) --S--C₁₋₆ alkyl;

W is O or (H, OH);

X, Y and Z are independently, selected from:

(a) hydrogen,

C₁₋₇ alkyl,

(c) C₂₋₆ alkenyl,

(d) halogen,

(e) --(CH₂)_(m) --NR⁶ R⁷, wherein R⁶ and R⁷ are, independently selectedfrom

(i) hydrogen, or

(ii) C₁₋₆ alkyl unsubstituted or substituted with phenyl, and m is 0 to2,

(f) --CN,

(g) --CHO,

(h) --CF₃,

(i) --SR⁸, wherein R⁸ is hydrogen, C₁₋₆ alkyl, trifluoromethyl, orphenyl,

(j) --SOR⁸, wherein R⁸ is as defined above,

(k) --SO₂ R⁸, wherein R⁸ is as defined above,

(l) --CONR⁶ R⁷, wherein R⁶ and R⁷ are as defined above,

(m) R⁹ O(CH₂)_(m) -- wherein R⁹ is hydrogen, C₁₋₃ alkyl, hydroxy-C₂₋₃alkyl, trifluoromethyl, phenyl or naphthyl and m is as defined above,

--(n) --CH(OR¹²)(OR¹³), wherein R¹² and R¹³ are C₁₋₃ alkyl or takentogether form an ethyl or propyl bridge,

(O) ##STR6## wherein R⁹ and m are as defined above, and (p) ##STR7##wherein R⁹ and m are as defined above, and (q) --OR¹¹ ;

or any two of adjacent X, Y and Z can be joined to form a ring having 5,6 or 7 ring atoms, said ring atoms comprising 1 or 2 oxygen atoms, theremaining ring atoms being carbon, selected from the group consistingof: dioxolanyl, dihydrofuranyl, dihydropyranyl, and dioxanyl; and

n is 1 or 2.

Another embodiment of the present invention encompasses the compounds ofFormula I wherein:

R¹ and R² are independently selected from:

(1) hydrogen;

(2) C₁₋₁₀ alkyl;

(3) substituted C₁₋₁₀ alkyl in which one or more substituent(s) is(are)selected from:

(a) hydroxy,

(b) oxo,

(c) C₁₋₆ -alkoxy,

(d) phenyl-C₁₋₃ alkoxy,

(e) substituted phenyl-C₁₋₃ alkoxy, in which the substituents on phenylare X, Y and Z,

(f) --OCO--C₁₋₆ alkyl,

(g) --NR⁶ R⁷, wherein R⁶ and R⁷ are independently selected from:

(i) hydrogen,

(ii) C₁₋₁₀ alkyl unsubstituted or substituted with one or more of thesubstituent(s) selected from:

(a') phenyl, which is unsubstituted or substituted with X, Y and Z,

(b') --OH,

(c') C₁₋₆ alkoxy,

(d') --CO₂ H,

(e') --CO₂ --C₁₋₆ alkyl,

(f') --C₃₋₇ cycloalkyl, and

(g') --OR¹¹,

(iii) C₃₋₁₀ alkenyl unsubstituted or substituted with one or more of thesubstituent(s) selected from:

(a') phenyl, which is unsubstituted or substituted with X, Y and Z,

(b') --OH,

(c') C₁₋₆ alkoxy,

(d') --CO₂ H,

(e') --CO₂ --C₁₋₆ alkyl,

(f') --C₃₋₇ cycloalkyl, and

(g') --OR¹¹,

(iv) or where R⁶ and R⁷ and the N to which they are attached can form anunsubstituted or substituted 3-7-membered saturated heterocyclic ringwhich can include one or two additional heteroatoms independentlyselected from the group consisting of O, S(O)_(p), NR¹⁴, wherein R¹⁴ ishydrogen or C₁₋₆ alkyl unsubstituted or substituted by phenyl, and p is0, 1 or 2, the ring being selected from the group consisting of:aziridine, morpholine, thiomorpholine, thiomorpholine-oxide,thiomorpholine-dioxide, piperidine, pyrrolidine, and piperazine,

(h) --NR⁶ CO--C₁₋₆ alkyl-R⁷, wherein R⁶ is as defined above,

(i) --NR⁶ CO₂ --C₁₋₆ alkyl-R⁷,

(j) --NR⁶ CONR⁶ R⁷,

(k) --OCONR⁶ R⁷,

(l) --COOR⁶,

(m) --CHO,

(n) phenyl,

(o) substituted phenyl in which the substituents are X, Y and Z,

(p) phenyloxy,

(q) substituted phenyloxy in which the substituents are X, Y and Z,

(r) 1- or 2-naphthyl,

(s) substituted 1- or 2-naphthyl in which the substituents are X, Y andZ,

(t) biphenyl,

(u) substituted biphenyl in which the substituents are X, Y and Z;

(v) --OR11, and

(w) --S(O)_(p) --C₁₋₆ alkyl;

(4) C₃₋₁₀ alkenyl;

(5) substituted C₃₋₁₀ alkenyl in which one or more substituent(s)is(are) selected from:

(a) hydroxy,

(b) oxo,

(c) C₁₋₆ alkoxy,

(d) phenyl-C₁₋₃ alkoxy,

(e) substituted phenyl-C₁₋₃ alkoxy, in which the substituents on phenylare X, Y and Z,

(f) --OCO--C₁₋₆ alkyl,

(g) --NR⁶ R⁷, wherein R⁶ and R⁷ are as defined above,

(h) --NR⁶ CO--C₁₋₆ alkyl, wherein R⁶ is as defined above,

(i) --COOR⁶, wherein R⁶ is as defined above,

(j) --CHO,

(k) phenyl,

(l) substituted phenyl in which the substituents are X, Y and Z,

(m) 1- or 2-naphthyl,

(n) substituted 1- or 2-naphthyl in which the substituents are X, Y andZ,

(o) biphenyl,

(p) substituted biphenyl in which the substituents are X, Y and Z,

(q) --OR¹¹, and

(r) --S(O)_(p) --C₁₋₆ alkyl;

(6) C₃₋₁₀ alkynyl;

(7) substituted C₃₋₁₀ alkynyl in which one or more substituent(s)is(are) selected from:

(a) hydroxy,

(b) oxo,

(c) C₁₋₆ alkoxy,

(d) phenyl-C₁₋₃ alkoxy,

(e) substituted phenyl-C₁₋₃ alkoxy, in which the substituents on phenylare X, Y and Z,

(f) --OCO--C₁₋₆ alkyl,

(g) --NR⁶ R⁷, wherein R⁶ and R⁷ are as defined above,

(h) --NR⁶ CO--C₁₋₆ alkyl, wherein R⁶ is as defined above,

(i) --COOR⁶, wherein R⁶ is as defined above,

(j) --CHO,

(k) phenyl,

(l) substituted phenyl in which the substituents are X, Y and Z,

(m) 1- or 2-naphthyl,

(n) substituted 1- or 2-naphthyl in which the substituents are X, Y andZ,

(o) biphenyl,

(p) substituted biphenyl in which the substituents are X, Y and Z, and

(q) --OR¹¹ ;

with the proviso that R¹ and R² are not simultaneously hydrogen, methylor combinations thereof;

R³ is hydrogen, hydroxy, --OR¹¹ or C₁₋₆ alkoxy;

R⁴ is hydrogen, or R³ and R⁴ taken together form a double bond;

R⁵ is methyl, ethyl, propyl or allyl;

R¹¹ is selected from:

(a) --PO(OH)O--M⁺, wherein M⁺ is a positively charged inorganic ororganic counterion,

(b) --SO₃ --M⁺,

(c) --CO(CH₂)_(q) CO₂ --M⁺, wherein q is 1-3, and

(d) --CO--C₁₋₆ alkyl-NR⁶ R⁷, wherein R⁶ and R⁷ are as defined above andthe alkyl is unsubstituted or substituted with one or more substituentsselected from:

(i) hydroxy,

(ii) C₁₋₆ alkoxy,

(iii) --NR¹⁶ R¹⁷, wherein R¹⁶ and R¹⁷ are independently selected from:

(a') hydrogen, and

(b') C₁₋₆ alkyl,

(iv) --COOR⁶, wherein R⁶ is as defined above,

(v) phenyl,

(vi) substituted phenyl in which the substituents are X, Y and Z,

(vii) --SH, and

(viii) --S--C₁₋₆ alkyl;

W is O or (H, OH);

X, Y and Z independently are selected from:

(a) hydrogen,

(b) C₁₋₇ alkyl,

(c) C₂₋₆ alkenyl,

(d) halogen,

(e) --(CH₂)_(m) --NR⁶ R⁷, wherein R⁶ and R⁷ are as defined above, and mis 0 to 2,

(f) --CN,

(g) --CHO,

(h) --CF₃,

(i) --SR⁸, wherein R⁸ is hydrogen, C₁₋₆ alkyl, trifluoromethyl, orphenyl,

(j) --SOR⁸, wherein R⁸ is as defined above,

(k) --SO₂ R⁸, wherein R⁸ is as defined above,

(l) --CONR⁶ R⁷, wherein R⁶ and R⁷ are as defined above,

(m) R⁹ O(CH₂)_(m) -- wherein R⁹ is hydrogen, C₁₋₃ alkyl, hydroxy-C₂₋₃alkyl, trifluoromethyl, phenyl or naphthyl and m is as defined above,

(n) --CH(OR¹²)(OR¹³), wherein R¹² and R¹³ are C₁₋₃ alkyl or takentogether form an ethyl or propyl bridge,

(o) ##STR8## wherein R⁹ and m are as defined above, and (p) ##STR9##wherein R⁹ and m are as defined above, and (q) --OR¹¹ ;

or any two of adjacent X, Y and Z can be joined to form a ring having 5,6 or 7 ring atoms, said ring atoms comprising 1 or 2 oxygen atoms, theremaining ring atoms being carbon, selected from the group consistingof: dioxolanyl, dihydrofuranyl, dihydropyranyl, and dioxanyl; and

n is 1 or 2.

In the present invention it is preferred that in compounds of Formula I:

R¹ and R² are independently selected from:

(1) hydrogen;

(2) phenyl;

(3) substituted phenyl in which the substituents are X, Y and Z;

(4) 1- or 2-naphthyl;

(5) substituted 1- or 2-naphthyl in which the substituents are X, Y andZ;

(6) C₁₋₁₀ alkyl;

(7) substituted C₁₋₁₀ alkyl in which one or more substituent(s) is(are)selected from:

(a) hydroxy,

(b) oxo,

(c) C₁₋₆ -alkoxy,

(d) phenyl-C₁₋₃ alkoxy,

(e) substituted phenyl-C₁₋₃ alkoxy, in which the substituents on phenylare X, Y and Z,

(f) --OCO--C₁₋₆ alkyl,

(g) --NR⁶ R⁷, wherein R⁶ and R⁷ are independently selected from:

(i) hydrogen,

(ii) C₁₋₁₀ alkyl unsubstituted or substituted with one or more of thesubstituent(s) selected from:

(a') phenyl, which is unsubstituted or substituted with X, Y and Z,

(b') --OH,

(c') C₁₋₆ alkoxy,

(d') --CO₂ H,

(e') --CO₂ --C₁₋₆ alkyl,

(f') --C₃₋₇ cycloalkyl, and

(g') --OR¹¹,

(iii) C₃₋₁₀ alkenyl unsubstituted or substituted with one or more of thesubstituent(s) selected from:

(a') phenyl, which is unsubstituted or substituted with X, Y and Z,

(b') --OH,

(c') C₁₋₆ alkoxy,

(d') --CO₂ H,

(e') --CO₂ --C₁₋₆ alkyl,

(f') --C₃₋₇ cycloalkyl, and

(g') --OR¹¹,

(iv) or where R⁶ and R⁷ and the N to which they are attached may form anunsubstituted or substituted 3-7-membered saturated heterocyclic ringwhich may include one or two additional heteroatoms independentlyselected from the group consisting of O, S(O)_(p), NR¹⁴, wherein R¹⁴ ishydrogen or C₁₋₆ alkyl unsubstituted or substituted by phenyl, and p is0, 1 or 2, the ring being selected from the group consisting of:aziridine, morpholine, thiomorpholine, thiomorpholine-oxide,thiomorpholine-dioxide, piperidine, pyrrolidine, and piperazine,

(h) --NR⁶ CO--C₁₋₆ alkyl-R⁷, wherein R⁶ is as defined above,

(i) --NR⁶ CO₂ --C₁₋₆ alkyl-R⁷,

(j) --NR⁶ CONR⁶ R⁷,

(k) --OCONR⁶ R⁷,

(l) --COOR⁶,

(m) --CHO,

(n) phenyl,

(o) substituted phenyl in which the substituents are X, Y and Z,

(p) phenyloxy,

(q) substituted phenyloxy in which the substituents are X, Y and Z,

(r) 1- or 2-naphthyl,

(s) substituted 1- or 2- and naphthyl in which the substituents are X, Yand Z, and

(t) --OR¹¹ ;

(8) C₃₋₁₀ alkenyl;

(9) substituted C₃₋₁₀ alkenyl in which one or more substituent(s)is(are) selected from:

(a) hydroxy,

(b) oxo,

(c) C₁₋₆ alkoxy,

(d) --OCOC₁₋₆ alkyl,

(e) C₂₋₈ alkenyl,

(f) phenyl,

(g) substituted phenyl in which the substituents are X, Y and Z,

(h) 1- or 2-naphthyl, and

(i) substituted 1- or 2-naphthyl in which the substituents are X, Y andZ,

(10) C₃₋₁₀ alkynyl;

(11) substituted C₃₋₁₀ alkynyl in which one or more substituent(s)is(are) selected from:

(a) hydroxy,

(b) oxo,

(c) C₁₋₆ alkoxy,

(d) --OCOC₁₋₆ alkyl,

(e) phenyl,

(f) substituted phenyl in which the substituents are X, Y and Z,

(g) 1- or 2-naphthyl, and

(h) substituted 1- or 2-naphthyl in which the substituents are X, Y andZ;

with the proviso that R¹ and R² are not simultaneously hydrogen, methylor combinations thereof;

R³ is hydrogen, or hydroxy;

R⁴ is hydrogen;

R⁵ is ethyl, propyl or allyl;

R¹¹ is selected from:

(a) --PO(OH)O--M⁺, wherein M⁺ is a positively charged inorganic ororganic counterion,

(b) --SO₃ --M⁺,

(c) --CO(CH₂)_(q) CO₂ ⁻ M⁺, wherein q is 1-3, and

(d) --CO--C₁₋₆ alkyl-NR⁶ R⁷, wherein R⁶ and R⁷ are as defined above andthe alkyl is unsubstituted or substituted with one or more substituentsselected from:

(i) hydroxy,

(ii) C₁₋₆ alkoxy,

(iii) --NR¹⁶ R¹⁷, wherein R¹⁶ and R¹⁷ are independently selected from:

(a') hydrogen, and

(b') C₁₋₆ alkyl,

(iv) --COOR⁶, wherein R⁶ is as defined above,

(v) phenyl,

(vi) substituted phenyl in which the substituents are X, Y and Z,

(vii) --SH, and

(viii) --S--C₁₋₆ alkyl;

W is O or (H, OH);

X, Y and Z independently are selected from:

(a) hydrogen,

(b) C₁₋₇ alkyl,

(c) C₂₋₆ alkenyl,

(d) halogen,

(e) --CN,

(f) --CHO,

(g) --CF₃,

(h) --SR⁸, wherein R⁸ is hydrogen, C₁₋₆ alkyl, trifluoromethyl, orphenyl,

(i) --CONR⁶ R⁷, wherein R⁶ and R⁷ are as defined above,

(j) R⁹ O(CH₂)_(m) -- wherein R⁹ is hydrogen, C₁₋₃ alkyl, hydroxy-C₂₋₃alkyl, trifluoromethyl, phenyl or naphthyl and m is as defined above,

(k) --CH(OR¹²)(OR¹³), wherein R¹² and R¹³ are C₁₋₃ alkyl or takentogether form an ethyl or propyl bridge,

(l) ##STR10## wherein R⁹ and m are as defined above, (m) ##STR11##wherein R⁹ and m are as defined above, and; (n) --OR¹¹ ;

or any two of adjacent X, Y and Z may be joined to form a ring having 5,6 or 7 ring atoms, said ring atoms comprising 1 or 2 oxygen atoms, theremaining ring atoms being carbon, selected from the group consistingof: dioxolanyl, dihydrofuranyl, dihydropyranyl, and dioxanyl; and

n is 2;

and pharmaceutically acceptable salts thereof.

Representative compounds of the present invention include the compoundsof Formula V, VI, VII and VIII: ##STR12## wherein R¹⁶ is H, methyl,ethyl, allyl or benzyl, R³ is OH or H and R¹⁵ and R² are selected fromthe following groups of substituents:

    ______________________________________                                        R.sup.15        R.sup.2                                                       ______________________________________                                        H               H                                                             2-F             H                                                             2-Cl            H                                                             2-Br            H                                                             2-CN            H                                                             2-CH.sub.3      H                                                             2-CF.sub.3      H                                                             2-CH.sub.3 CH.sub.2                                                                           H                                                             2-OH            H                                                             2-NO.sub.2      H                                                             2-NH.sub.2      H                                                             2-CF.sub.3 O    H                                                             2-CH.sub.3 O    H                                                             2-CH.sub.3 CH.sub.2 O                                                                         H                                                             2-CH.sub.3 S    H                                                             2-CH.sub.3 S(O) H                                                             2-CH.sub.3 SO.sub.2                                                                           H                                                             3-F             H                                                             3-Cl            H                                                             3-Br            H                                                             3-CN            H                                                             3-CH.sub.3      H                                                             3-CF.sub.3      H                                                             3-CH.sub.3 CH.sub.2                                                                           H                                                             3-OH            H                                                             3-NO.sub.2      H                                                             3-NH.sub.2      H                                                             3-CF.sub.3 O    H                                                             3-CH.sub.3 O    H                                                             3-CH.sub.3 CH.sub.2 O                                                                         H                                                             3-CH.sub.3 S    H                                                             3-CH.sub.3 S(O) H                                                             3-CH.sub.3 SO.sub.2                                                                           H                                                             4-F             H                                                             4-Cl            H                                                             4-Br            H                                                             4-CN            H                                                             4-CH.sub.3      H                                                             4-CF.sub.3      H                                                             4-CH.sub.3 CH.sub.2                                                                           H                                                             4-OH            H                                                             4-NO.sub.2      H                                                             4-NH.sub.2      H                                                             4-CF.sub.3 O    H                                                             4-CH.sub.3 O    H                                                             4-CH.sub.3 CH.sub.2 O                                                                         H                                                             4-CH.sub.3 S    H                                                             4-CH.sub.3 S(O) H                                                             4-CH.sub.3 SO.sub.2                                                                           H                                                             3,5-di-F        H                                                             3,5-di-Cl       H                                                             3,5-di-Br       H                                                             3,5-di-CH.sub.3 H                                                             3,5-di-CH.sub.3 CH.sub.2                                                                      H                                                             3,5-di-CH.sub.3 O                                                                             H                                                             3,5-di-CH.sub.3 CH.sub.2 O                                                                    H                                                             H               CH.sub.3                                                      2-F             CH.sub.3                                                      2-Cl            CH.sub.3                                                      2-Br            CH.sub.3                                                      2-CN            CH.sub.3                                                      2-CH.sub.3      CH.sub.3                                                      2-CF.sub.3      CH.sub.3                                                      2-CH.sub.3 CH.sub.2                                                                           CH.sub.3                                                      2-OH            CH.sub.3                                                      2-NO.sub.2      CH.sub.3                                                      2-NH.sub.2      CH.sub.3                                                      2-CF.sub.3 O    CH.sub.3                                                      2-CH.sub.3 O    CH.sub.3                                                      2-CH.sub.3 CH.sub.2 O                                                                         CH.sub.3                                                      2-CH.sub.3 S    CH.sub.3                                                      2-CH.sub.3 S(O) CH.sub.3                                                      2-CH.sub.3 SO.sub.2                                                                           CH.sub.3                                                      3-F             CH.sub.3                                                      3-Cl            CH.sub.3                                                      3-Br            CH.sub.3                                                      3-CN            CH.sub.3                                                      3-CH.sub.3      CH.sub.3                                                      3-CF.sub.3      CH.sub.3                                                      3-CH.sub.3 CH.sub.2                                                                           CH.sub.3                                                      3-OH            CH.sub.3                                                      3-NO.sub.2      CH.sub.3                                                      3-NH.sub.2      CH.sub.3                                                      3-CF.sub.3 O    CH.sub.3                                                      3-CH.sub.3 O    CH.sub.3                                                      3-CH.sub.3 CH.sub.2 O                                                                         CH.sub.3                                                      3-CH.sub.3 S    CH.sub.3                                                      3-CH.sub.3 S(O) CH.sub.3                                                      3-CH.sub.3 SO.sub.2                                                                           CH.sub.3                                                      4-F             CH.sub.3                                                      4-Cl            CH.sub.3                                                      4-Br            CH.sub.3                                                      4-CN            CH.sub.3                                                      4-CH.sub.3      CH.sub.3                                                      4-CF.sub.3      CH.sub.3                                                      4-CH.sub.3 CH.sub.2                                                                           CH.sub.3                                                      4-OH            CH.sub.3                                                      4-NO.sub.2      CH.sub.3                                                      4-NH.sub.2      CH.sub.3                                                      4-CF.sub.3 O    CH.sub.3                                                      4-CH.sub.3 O    CH.sub.3                                                      4-CH.sub.3 CH.sub.2 O                                                                         CH.sub.3                                                      4-CH.sub.3 S    CH.sub.3                                                      4-CH.sub.3 S(O) CH.sub.3                                                      4-CH.sub.3 SO.sub.2                                                                           CH.sub.3                                                      3,5-di-F        CH.sub.3                                                      3,5-di-Cl       CH.sub.3                                                      3,5-di-Br       CH.sub.3                                                      3,5-di-CH.sub.3 CH.sub.3                                                      3,5-di-CH.sub.3 CH.sub.2                                                                      CH.sub.3                                                      3,5-di-CH.sub.3 O                                                                             CH.sub.3                                                      3,5-di-CH.sub.3 CH.sub.2 O                                                                    CH.sub.3                                                      H               CH.sub.3 CH.sub.2                                             2-F             CH.sub.3 CH.sub.2                                             2-Cl            CH.sub.3 CH.sub.2                                             2-Br            CH.sub.3 CH.sub.2                                             2-CN            CH.sub.3 CH.sub.2                                             2-CH.sub.3      CH.sub.3 CH.sub.2                                             2-CF3           CH.sub.3 CH.sub.2                                             2-CH.sub.3 CH.sub.2                                                                           CH.sub.3 CH.sub.2                                             2-OH            CH.sub.3 CH.sub.2                                             2-NO.sub.2      CH.sub.3 CH.sub.2                                             2-NH.sub.2      CH.sub.3 CH.sub.2                                             2-CF.sub.3 O    CH.sub.3 CH.sub.2                                             2-CH.sub.3 O    CH.sub.3 CH.sub.2                                             2-CH.sub.3 CH.sub.2 O                                                                         CH.sub.3 CH.sub.2                                             2-CH.sub.3 S    CH.sub.3 CH.sub.2                                             2-CH.sub.3 S(O) CH.sub.3 CH.sub.2                                             2-CH.sub.3 SO.sub.2                                                                           CH.sub.3 CH.sub.2                                             3-F             CH.sub.3 CH.sub.2                                             3-Cl            CH.sub.3 CH.sub.2                                             3-Br            CH.sub.3 CH.sub.2                                             3-CN            CH.sub.3CH.sub.2                                              3-CH.sub.3      CH.sub.3 CH.sub.2                                             3-CF.sub.3      CH.sub.3 CH.sub.2                                             3-CH.sub.3 CH.sub.2                                                                           CH.sub.3 CH.sub.2                                             3-OH            CH.sub.3 CH.sub.2                                             3-NO.sub.2      CH.sub.3 CH.sub.2                                             3-NH.sub.2      CH.sub.3 CH.sub.2                                             3-CF.sub.3 O    CH.sub.3 CH.sub.2                                             3-CH.sub.3 O    CH.sub.3 CH.sub.2                                             3-CH.sub.3 CH.sub.2 O                                                                         CH.sub.3 CH.sub.2                                             3-CH.sub.3 S    CH.sub.3 CH.sub.2                                             3-CH.sub.3 S(O) CH.sub.3 CH.sub.2                                             3-CH.sub.3 SO.sub.2                                                                           CH.sub.3 CH.sub.2                                             4-F             CH.sub.3 CH.sub.2                                             4-Cl            CH.sub.3 CH.sub.2                                             4-Br            CH.sub.3 CH.sub.2                                             4-CN            CH.sub.3 CH.sub.2                                             4-CH.sub.3      CH.sub.3 CH.sub.2                                             4-CF.sub.3      CH.sub.3 CH.sub.2                                             4-CH.sub.3 CH.sub.2                                                                           CH.sub.3 CH.sub.2                                             4-OH            CH.sub.3 CH.sub.2                                             4-NO.sub.2      CH.sub.3 CH.sub.2                                             4-NH.sub.2      CH.sub.3 CH.sub.2                                             4-CF.sub.3 O    CH.sub.3 CH.sub.2                                             4-CH.sub.3 O    CH.sub.3 CH.sub.2                                             4-CH.sub.3 CH.sub.2 0                                                                         CH.sub.3 CLH.sub.2                                            4-CH.sub.3 S    CH.sub.3 CH.sub.2                                             4-CH.sub.3 S(O) CH.sub.3 CH.sub.2                                             4-CH.sub.3 SO.sub.2                                                                           CH.sub.3 CH.sub.2                                             3,5-di-F        CH.sub.3 CH.sub.2                                             3,5-di-Cl       CH.sub.3 CH.sub.2                                             3,5-di-Br       CH.sub.3 CH.sub.2                                             3,5-di-CH.sub.3 CH.sub.3 CH.sub.2                                             3,5-di-CH.sub.3 CH.sub.2                                                                      CH.sub.3 CH.sub.2                                             3,5-di-CH.sub.3 O                                                                             CH.sub.3 CH.sub.2                                             3,5-di-CH.sub.3 CH.sub.2 O                                                                    CH.sub.3 CH.sub.2                                             H               allyl                                                         2-F             allyl                                                         2-Cl            allyl                                                         2-Br            allyl                                                         2-CN            ally1                                                         2-CH.sub.3      allyl                                                         2-CF.sub.3      allyl                                                         2-CH.sub.3 CH.sub.2                                                                           allyl                                                         2-OH            allyl                                                         2-NO.sub.2      allyl                                                         2-NH.sub.2      allyl                                                         2-CF.sub.3 O    allyl                                                         2-CH.sub.3 O    allyl                                                         2-CH.sub.3 CH.sub.2 O                                                                         allyl                                                         2-CH.sub.3 S    allyl                                                         2-CH.sub.3 S(O) allyl                                                         2-CH.sub.3 SO.sub.2                                                                           allyl                                                         3-F             allyl                                                         3-Cl            allyl                                                         3-Br            allyl                                                         3-CN            allyl                                                         3-CH.sub.3      allyl                                                         3-CF.sub.3      allyl                                                         3-CH.sub.3 CH.sub.2                                                                           allyl                                                         3-OH            allyl                                                         3-NO.sub.2      allyl                                                         3-NH.sub.2      allyl                                                         3-CF.sub.3 O    allyl                                                         3-CH.sub.3 O    allyl                                                         3-CH.sub.3 CH.sub.2 O                                                                         allyl                                                         3-CH.sub.3 S    allyl                                                         3-CH.sub.3 S(O) allyl                                                         3-CH.sub.3 SO.sub.2                                                                           allyl                                                         4-F             allyl                                                         4-Cl            allyl                                                         4-Br            allyl                                                         4-CN            allyl                                                         4-CH.sub.3      allyl                                                         4-CF.sub.3      allyl                                                         4-CH.sub.3 CH.sub.2                                                                           allyl                                                         4-OH            allyl                                                         4-NO.sub.2      allyl                                                         4-NH.sub.2      allyl                                                         4-CF.sub.3 O    allyl                                                         4-CH.sub.3 O    allyl                                                         4-CH.sub.3 CH.sub.2 O                                                                         allyl                                                         4-CH.sub.3 S    allyl                                                         4-CH.sub.3 S(O) allyl                                                         4-CH.sub.3 SO.sub.2                                                                           allyl                                                         3,5-di-F        allyl                                                         3,5-di-Cl       allyl                                                         3,5-di-Br       allyl                                                         3,5-di-CH.sub.3 allyl                                                         3,5-di-CH.sub.3 CH.sub.2                                                                      allyl                                                         3,5-di-CH.sub.3 O                                                                             allyl                                                         3,5-di-CH.sub.3 CH.sub.2 O                                                                    allyl                                                         H               CH.sub.3 CH.sub.2 CH.sub.2                                    2-F             CH.sub.3 CH.sub.2 CH.sub.2                                    2-Cl            CH.sub.3 CH.sub.2 CH.sub.2                                    2-Br            CH.sub.3 CH.sub.2 CH.sub.2                                    2-CN            CH.sub.3 CH.sub.2 CH.sub.2                                    2-CH.sub.3      CH.sub.3 CH.sub.2 CH.sub.2                                    2-CF.sub.3      CH.sub.3 CH.sub.2 CH.sub.2                                    2-CH.sub.3 CH.sub.2                                                                           CH.sub.3 CH.sub.2 CH.sub.2                                    2-OH            CH.sub.3 CH.sub.2 CH.sub.2                                    2-NO.sub.2      CH.sub.3 CH.sub.2 CH.sub.2                                    2-NH.sub.2      CH.sub.3 CH.sub.2 CH.sub.2                                    2-CF.sub.3 O    CH.sub.3 CH.sub.2 CH.sub.2                                    2-CH.sub.3 O    CH.sub.3 CH.sub.2 CH.sub.2                                    2-CH.sub.3 CH.sub.2 O                                                                         CH.sub.3 CH.sub.2 CH.sub.2                                    2-CH.sub.3 S    CH.sub.3 CH.sub.2 CH.sub.2                                    2-CH.sub.3 S(O) CH.sub.3 CH.sub.2 CH.sub.2                                    2-CH.sub.3 SO.sub.2                                                                           CH.sub.3 CH.sub.2 CH.sub.2                                    3-F             CH.sub.3 CH.sub.2 CH.sub.2                                    3-Cl            CH.sub.3 CH.sub.2 CH.sub.2                                    3-Br            CH.sub.3 CH.sub.2 CH.sub.2                                    3-CN            CH.sub.3 CH.sub.2 CH.sub.2                                    3-CH.sub.3      CH.sub.3 CH.sub.2 CH.sub.2                                    3-CF.sub.3      CH.sub.3 CH.sub.2 CH.sub.2                                    3-CH.sub.3 CH.sub.2                                                                           CH.sub.3 CH.sub.2 CH.sub.2                                    3-OH            CH.sub.3 CH.sub.2 CH.sub.2                                    3-NO.sub.2      CH.sub.3 CH.sub.2 CH.sub.2                                    3-NH.sub.2      CH.sub.3 CH.sub.2 CH.sub.2                                    3-CH.sub.3 O    CH.sub.3 CH.sub.2 CH.sub.2                                    3-CH.sub.3 CH.sub.2 O                                                                         CH.sub.3 CH.sub.2 CH.sub.2                                    3-CH.sub.3 S    CH.sub.3 CH.sub.2 CH.sub.2                                    3-CH.sub.3 S(O) CH.sub.3 CH.sub.2 CH.sub.2                                    3-CH.sub.3 SO.sub.2                                                                           CH.sub.3 CH.sub.2 CH.sub.2                                    4-F             CH.sub.3 CH.sub.2 CH.sub.2                                    4-Cl            CH.sub.3 CH.sub.2 CH.sub.2                                    4-Br            CH.sub.3 CH.sub.2 CH.sub.2                                    4-CN            CH.sub.3 CH.sub.2 CH.sub.2                                    4-CH.sub.3      CH.sub.3 CH.sub.2 CH.sub.2                                    4-CF.sub.3      CH.sub.3 CH.sub.2 CH.sub.2                                    4-CH.sub.3 CH.sub.2                                                                           CH.sub.3 CH.sub.2 CH.sub.2                                    4-OH            CH.sub.3 CH.sub.2 CH.sub.2                                    4-NO.sub.2      CH.sub.3 CH.sub.2 CH.sub.2                                    4-NH.sub.2      CH.sub.3 CH.sub.2 CH.sub.2                                    4-CF.sub.3 O    CH.sub.3 CH.sub.2 CH.sub.2                                    4-CH.sub.3 O    CH.sub.3 CH.sub.2 CH.sub.2                                    4-CH.sub.3 CH.sub.2 O                                                                         CH.sub.3 CH.sub.2 CH.sub.2                                    4-CH.sub.3 S    CH.sub.3 CH.sub.2 CH.sub.2                                    4-CH.sub.3 S(O) CH.sub.3 CH.sub.2 CH.sub.2                                    4-CH.sub.3 SO.sub.2                                                                           CH.sub.3 CH.sub.2 CH.sub.2                                    3,5-di-F        CH.sub.3 CH.sub.2 CH.sub.2                                    3,5-di-Cl       CH.sub.3 CH.sub.2 CH.sub.2                                    3,5-di-Br       CH.sub.3 CH.sub.2 CH.sub.2                                    3,5-di-CH.sub.3 CH.sub.3 CH.sub.2 CH.sub.2                                    3,5-di-CH.sub.3 CH.sub.2                                                                      CH.sub.3 CH.sub.2 CH.sub.2                                    3,5-di-CH.sub.3 O                                                                             CH.sub.3 CH.sub.2 CH.sub.2                                    3,5-di-CH.sub.3 CH.sub.2 O                                                                    CH.sub.3 CH.sub.2 CH.sub.2                                    H               HOCH.sub.2 CH.sub.2                                           2-F             HOCH.sub.2 CH.sub.2                                           2-Cl            HOCH.sub.2 CH.sub.2                                           2-Br            HOCH.sub.2 CH.sub.2                                           2-CN            HOCH.sub.2 CH.sub.2                                           2-CH.sub.3      HOCH.sub.2 CH.sub.2                                           2-CF.sub.3      HOCH.sub.2 CH.sub.2                                           2-CH.sub.3 CH.sub.2                                                                           HOCH.sub.2 CH.sub.2                                           2-OH            HOCH.sub.2 CH.sub.2                                           2-NO.sub.2      HOCH.sub.2 CH.sub.2                                           2-NH.sub.2      HOCH.sub.2 CH.sub.2                                           2-CF.sub.3 O    HOCH.sub.2 CH.sub.2                                           2-CH.sub.3 O    HOCH.sub.2 CH.sub.2                                           2-CH.sub.3 CH.sub.2 O                                                                         HOCH.sub.2 CH.sub.2                                           2-CH.sub.3 S    HOCH.sub.2 CH.sub.2                                           2-CH.sub.3 S(O) HOCH.sub.2 CH.sub.2                                           2-CH.sub.3 SO.sub.2                                                                           HOCH.sub.2 CH.sub.2                                           3-F             HOCH.sub.2 CH.sub.2                                           3-Cl            HOCH.sub.2 CH.sub.2                                           3-Br            HOCH.sub.2 CH.sub.2                                           3-CN            HOCH.sub.2 CH.sub.2                                           3-CH.sub.3      HOCH.sub.2 CH.sub.2                                           3-CF.sub.3      HOCH.sub.2 CH.sub.2                                           3-CH.sub.3 CH.sub.2                                                                           HOCH.sub.2 CH.sub.2                                           3-OH            HOCH.sub.2 CH.sub.2                                           3-NO.sub.2      HOCH.sub.2 CH.sub.2                                           3-NH.sub.2      HOCH.sub.2 CH.sub.2                                           3-CF.sub.3 O    HOCH.sub.2 CH.sub.2                                           3-CH.sub.3 O    HOCH.sub.2 CH.sub.2                                           3-CH.sub.3 CH.sub.2 O                                                                         HOCH.sub.2 CH.sub.2                                           3-CH.sub.3 S    HOCH.sub.2 CH.sub.2                                           3-CH.sub.3 S(O) HOCH.sub.2 CH.sub.2                                           3-CH.sub.3 SO.sub.2                                                                           HOCH.sub.2 CH.sub.2                                           4-F             HOCH.sub.2 CH.sub.2                                           4-Cl            HOCH.sub.2 CH.sub.2                                           4-Br            HOCH.sub.2 CH.sub.2                                           4-CN            HOCH.sub.2 CH.sub.2                                           4-CH.sub.3      HOCH.sub.2 CH.sub.2                                           4-CF.sub.3      HOCH.sub.2 CH.sub.2                                           4-CH.sub.3 CH.sub.2                                                                           HOCH.sub.2 CH.sub.2                                           4-OH            HOCH.sub.2 CH.sub.2                                           4-NO.sub.2      HOCH.sub.2 CH.sub.2                                           4-NH.sub.2      HOCH.sub.2 CH.sub.2                                           4-CF.sub.3 O    HOCH.sub.2 CH.sub.2                                           4-CH.sub.3 O    HOCH.sub.2 CH.sub.2                                           4-CH.sub.3 CH.sub.2 O                                                                         HOCH.sub.2 CH.sub.2                                           4-CH.sub.3 S    HOCH.sub.2 CH.sub.2                                           4-CH.sub.3 S(O) HOCH.sub.2 CH.sub.2                                           4-CH.sub.3 SO.sub.2                                                                           HOCH.sub.2 CH.sub.2                                           3,5-di-F        HOCH.sub.2 CH.sub.2                                           3,5-di-Cl       HOCH.sub.2 CH.sub.2                                           3,5-di-Br       HOCH.sub.2 CH.sub.2                                           3,5-di-CH.sub.3 HOCH.sub.2 CH.sub.2                                           3,5-di-CH.sub.3 CH.sub.2                                                                      HOCH.sub.2 CH.sub.2                                           3,5-di-CH.sub.3 O                                                                             HOCH.sub.2 CH.sub.2                                           3,5-di-CH.sub.3 CH.sub.2 O                                                                    HOCH.sub.2 CH.sub.2                                           H               (CH.sub.3).sub.2 CH                                           2-F             (CH.sub.3).sub.2 CH                                           2-Cl            (CH.sub.3).sub.2 CH                                           2-Br            (CH.sub.3).sub.2 CH                                           2-CN            (CH.sub.3).sub.2 CH                                           2-CH.sub.3      (CH.sub.3).sub.2 CH                                           2-CF.sub.3      (CH.sub.3).sub.2 CH                                           2-CH.sub.3 CH.sub.2                                                                           (CH.sub.3).sub.2 CH                                           2-OH            (CH.sub.3).sub.2 CH                                           2-NO.sub.2      (CH.sub.3).sub.2 CH                                           2-NH.sub.2      (CH.sub.3).sub.2 CH                                           2-CF.sub.3 O    (CH.sub.3).sub.2 CH                                           2-CH.sub.3 O    (CH.sub.3).sub.2 CH                                           2-CH.sub.3 CH.sub.2 O                                                                         (CH.sub.3).sub.2 CH                                           2-CH.sub.3 S    (CH.sub.3).sub.2 CH                                           2-CH.sub.3 S(O) (CH.sub.3).sub.2 CH                                           2-CH.sub.3 SO.sub.2                                                                           (CH.sub.3).sub.2 CH                                           3-F             (CH.sub.3).sub.2 CH                                           3-Cl            (CH.sub.3).sub.2 CH                                           3-Br            (CH.sub.3).sub.2 CH                                           3-CN            (CH.sub.3).sub.2 CH                                           3-CH.sub.3      (CH.sub.3).sub.2 CH                                           3-CF.sub.3      (CH.sub.3).sub.2 CH                                           3-CH.sub.3 CH.sub.2                                                                           (CH.sub.3).sub.2 CH                                           3-OH            (CH.sub.3).sub.2 CH                                           3-NO.sub.2      (CH.sub.3).sub.2 CH                                           3-NH.sub.2      (CH.sub.3).sub.2 CH                                           3-CF.sub.3 O    (CH.sub.3).sub.2 CH                                           3-CH.sub.3 O    (CH.sub.3).sub.2 CH                                           3-CH.sub.3 CH.sub.2 O                                                                         (CH.sub.3).sub.2 CH                                           3-CH.sub.3 S    (CH.sub.3).sub.2 CH                                           3-CH.sub.3 S(O) (CH.sub.3).sub.2 CH                                           3-CH.sub.3 SO.sub.2                                                                           (CH.sub.3).sub.2 CH                                           4-F             (CH.sub.3).sub.2 CH                                           4-Cl            (CH.sub.3).sub.2 CH                                           4-Br            (CH.sub.3).sub.2 CH                                           4-CN            (CH.sub.3).sub.2 CH                                           4-CH.sub.3      (CH.sub.3).sub.2 CH                                           4-CF.sub.3      (CH.sub.3).sub.2 CH                                           4-CH.sub.3 CH.sub.2                                                                           (CH.sub.3).sub.2 CH                                           4-OH            (CH.sub.3).sub.2 CH                                           4-NO.sub.2      (CH.sub.3).sub.2 CH                                           4-NH.sub.2      (CH.sub.3).sub.2 CH                                           4-CF.sub.3 O    (CH.sub.3).sub.2 CH                                           4-CH.sub.3 O    (CH.sub.3).sub.2 CH                                           4-CH.sub.3 CH.sub.2 O                                                                         (CH.sub.3).sub.2 CH                                           4-CH.sub.3 S    (CH.sub.3).sub.2 CH                                           4-CH.sub.3 S(O) (CH.sub.3).sub.2 CH                                           4-CH.sub.3 SO.sub.2                                                                           (CH.sub.3).sub.2 CH                                           3,5-di-F        (CH.sub.3).sub.2 CH                                           3,5-di-Cl       (CH.sub.3).sub.2 CH                                           3,5-di-Br       (CH.sub.3).sub.2 CH                                           3,5-di-CH.sub.3 (CH.sub.3).sub.2 CH                                           3,5-di-CH.sub.3 CH.sub.2                                                                      (CH.sub.3).sub.2 CH                                           3,5-di-CH.sub.3 O                                                                             (CH.sub.3).sub.2 CH                                           3,5-di-CH.sub.3 CH.sub.2 O                                                                    (CH.sub.3).sub.2 CH                                           ______________________________________                                    

Representative compounds of the present invention include the compoundsof Formula IX and X: ##STR13## wherein R¹⁷ and R¹⁸ are hydrogen, methylor ethyl and R³ is OH or H and R¹⁵ and R² are selected from thefollowing groups of substituents:

    ______________________________________                                        R.sup.15        R.sup.2                                                       ______________________________________                                        H               H                                                             2-F             H                                                             2-Cl            H                                                             2-Br            H                                                             2-CN            H                                                             2-CH.sub.3      H                                                             2-CF.sub.3      H                                                             2-CH.sub.3 CH.sub.2                                                                           H                                                             2-OH            H                                                             2-NO.sub.2      H                                                             2-NH.sub.2      H                                                             2-CF.sub.3 O    H                                                             2-CH.sub.3 O    H                                                             2-CH.sub.3 CH.sub.2 O                                                                         H                                                             2-CH.sub.3 S    H                                                             2-CH.sub.3 S(O) H                                                             2-CH.sub.3 SO.sub.2                                                                           H                                                             3-F             H                                                             3-Cl            H                                                             3-Br            H                                                             3-CN            H                                                             3-CH.sub.3      H                                                             3-CF.sub.3      H                                                             3-CH.sub.3 CH.sub.2                                                                           H                                                             3-OH            H                                                             3-NO.sub.2      H                                                             3-NH.sub.2      H                                                             3-CF.sub.3 O    H                                                             3-CH.sub.3 O    H                                                             3-CH.sub.3 CH.sub.2 O                                                                         H                                                             3-CH.sub.3 S    H                                                             3-CH.sub.3 S(O) H                                                             3-CH.sub.3 SO.sub.2                                                                           H                                                             4-F             H                                                             4-Cl            H                                                             4-Br            H                                                             4-CN            H                                                             4-CH.sub.3      H                                                             4-CF.sub.3      H                                                             4-CH.sub.3 CH.sub.2                                                           4-OH            H                                                             4-NO.sub.2      H                                                             4-NH.sub.2      H                                                             4-CF.sub.3 O    H                                                             4-CH.sub.3 O    H                                                             4-CH.sub.3 CH.sub.2 O                                                                         H                                                             4-CH.sub.3 S    H                                                             4-CH.sub.3 S(O) H                                                             4-CH.sub.3 SO.sub.2                                                           3,5-di-F        H                                                             3,5-di-Cl       H                                                             3,5-di-Br       H                                                             3,5-di-CH.sub.3 H                                                             3,5-di-CH.sub.3 CH.sub.2                                                                      H                                                             3,5-di-CH.sub.3 O                                                                             H                                                             3,5-di-CH.sub.3 CH.sub.2 O                                                                    H                                                             H               CH.sub.3                                                      2-F             CH.sub.3                                                      2-Cl            CH.sub.3                                                      2-Br            CH.sub.3                                                      2-CN            CH.sub.3                                                      2-CH.sub.3      CH.sub.3                                                      2-CF.sub.3      CH.sub.3                                                      2-CH.sub.3 CH.sub.2                                                                           CH.sub.3                                                      2-OH            CH.sub.3                                                      2-NO.sub.2      CH.sub.3                                                      2-NH.sub.2      CH.sub.3                                                      2-CF.sub.3 O    CH.sub.3                                                      2-CH.sub.3 O    CH.sub.3                                                      2-CH.sub.3 CH.sub.2 O                                                                         CH.sub.3                                                      2-CH.sub.3 S    CH.sub.3                                                      2-CH.sub.3 S(O) CH.sub.3                                                      2-CH.sub.3 SO.sub.2                                                                           CH.sub.3                                                      3-F             CH.sub.3                                                      3-Cl            CH.sub.3                                                      3-Br            CH.sub.3                                                      3-CN            CH.sub.3                                                      3-CH.sub.3      CH.sub.3                                                      3-CF.sub.3      CH.sub.3                                                      3-CH.sub.3 CH.sub.2                                                                           CH.sub.3                                                      3-OH            CH.sub.3                                                      3-NO.sub.2      CH.sub.3                                                      3-NH.sub.2      CH.sub.3                                                      3-CF.sub.3 O    CH.sub.3                                                      3-CH.sub.3 O    CH.sub.3                                                      3-CH.sub.3 CH.sub.2 O                                                                         CH.sub.3                                                      3-CH.sub.3 S    CH.sub.3                                                      3-CH.sub.3 S(O) CH.sub.3                                                      3-CH.sub.3 SO.sub.2                                                                           CH.sub.3                                                      4-F             CH.sub.3                                                      4-Cl            CH.sub.3                                                      4-Br            CH.sub.3                                                      4-CN            CH.sub.3                                                      4-CH.sub.3      CH.sub.3                                                      4-CF.sub.3      CH.sub.3                                                      4-CH.sub.3 CH.sub.2                                                                           CH.sub.3                                                      4-OH            CH.sub.3                                                      4-NO.sub.2      CH.sub.3                                                      4-NH.sub.2      CH.sub.3                                                      4-CF.sub.3 O    CH.sub.3                                                      4-CH.sub.3 O    CH.sub.3                                                      4-CH.sub.3 CH.sub.2 O                                                                         CH.sub.3                                                      4-CH.sub.3 S    CH.sub.3                                                      4-CH.sub.3 S(O) CH.sub.3                                                      4-CH.sub.3 SO.sub.2                                                                           CH.sub.3                                                      3,5-di-F        CH.sub.3                                                      3,5-di-Cl       CH.sub.3                                                      3,5-di-Br       CH.sub.3                                                      3,5-di-CH.sub.3 CH.sub.3                                                      3,5-di-CH.sub.3 CH.sub.2                                                                      CH.sub.3                                                      3,5-di-CH.sub.3 O                                                                             CH.sub.3                                                      3,5-di-CH.sub.3 CH.sub.2 O                                                                    CH.sub.3                                                      H               CH.sub.3 CH.sub.2                                             2-F             CH.sub.3 CH.sub.2                                             2-Cl            CH.sub.3 CH.sub.2                                             2-Br            CH.sub.3 CH.sub.2                                             2-CN            CH.sub.3 CH.sub.2                                             2-CH.sub.3      CH.sub.3 CH.sub.2                                             2-CF.sub.3      CH.sub.3 CH.sub.2                                             2-CH.sub.3 CH.sub.2                                                                           CH.sub.3 CH.sub.2                                             2-OH            CH.sub.3 CH.sub.2                                             2-NO.sub.2      CH.sub.3 CH.sub.2                                             2-NH.sub.2      CH.sub.3 CH.sub.2                                             2-CF.sub.3 O    CH.sub.3 CH.sub.2                                             2-CH.sub.3 O    CH.sub.3 CH.sub.2                                             2-CH.sub.3 CH.sub.2 O                                                                         CH.sub.3 CH.sub.2                                             2-CH.sub.3 S    CH.sub.3 CH.sub.2                                             2-CH.sub.3 S(O) CH.sub.3 CH.sub.2                                             2-CH.sub.3 SO.sub.2                                                                           CH.sub.3 CH.sub.2                                             3-F             CH.sub.3 CH.sub.2                                             3-Cl            CH.sub.3 CH.sub.2                                             3-Br            CH.sub.3 CH.sub.2                                             3-CN            CH.sub.3 CH.sub.2                                             3-CH.sub.3      CH.sub.3 CH.sub.2                                             3-CF.sub.3      CH.sub.3 CH.sub.2                                             3-CH.sub.3 CH.sub.2                                                                           CH.sub.3 CH.sub.2                                             3-OH            CH.sub.3 CH.sub.2                                             3-NO.sub.2      CH.sub.3 CH.sub.2                                             3-NH.sub.2      CH.sub.3 CH.sub.2                                             3-CF.sub.3 O    CH.sub.3 CH.sub.2                                             3-CH.sub.3 O    CH.sub.3 CH.sub.2                                             3-CH.sub.3 CH.sub.2 O                                                                         CH.sub.3 CH.sub.2                                             3-CH.sub.3 S    CH.sub.3 CH.sub.2                                             3-CH.sub.3 S(O) CH.sub.3 CH.sub.2                                             3-CH.sub.3 SO.sub.2                                                                           CH.sub.3 CH.sub.2                                             4-F             CH.sub.3 CH.sub.2                                             4-Cl            CH.sub.3 CH.sub.2                                             4-Br            CH.sub.3 CH.sub.2                                             4-CN            CH.sub.3 CH.sub.2                                             4-CH.sub.3      CH.sub.3 CH.sub.2                                             4-CF.sub.3      CH.sub.3 CH.sub.2                                             4-CH.sub.3 CH.sub.2                                                                           CH.sub.3 CH.sub.2                                             4-OH            CH.sub.3 CH.sub.2                                             4-NO.sub.2      CH.sub.3 CH.sub.2                                             4-NH.sub.2      CH.sub.3 CH.sub.2                                             4-CF.sub.3 O    CH.sub.3 CH.sub.2                                             4-CH.sub.3 O    CH.sub.3 CH.sub.2                                             4-CH.sub.3 CH.sub.2 O                                                                         CH.sub.3 CH.sub.2                                             4-CH.sub.3 S    CH.sub.3 CH.sub.2                                             4-CH.sub.3 S(O) CH.sub.3 CH.sub.2                                             4-CH.sub.3 SO.sub.2                                                                           CH.sub.3 CH.sub.2                                             3,5-di-F        CH.sub.3 CH.sub.2                                             3,5-di-Cl       CH.sub.3 CH.sub.2                                             3,5-di-Br       CH.sub.3 CH.sub.2                                             3,5-di-CH.sub.3 CH.sub.3 CH.sub.2                                             3,5-di-CH.sub.3 CH.sub.2                                                                      CH.sub.3 CH.sub.2                                             3,5-di-CH.sub.3 O                                                                             CH.sub.3 CH.sub.2                                             3,5-di-CH.sub.3 CH.sub.2 O                                                                    CH.sub.3 CH.sub.2                                             H               allyl                                                         2-F             allyl                                                         2-Cl            allyl                                                         2-Br            allyl                                                         2-CN            allyl                                                         2-CH.sub.3      allyl                                                         2-CF.sub.3      allyl                                                         2-CH.sub.3 CH.sub.2                                                                           allyl                                                         2-OH            allyl                                                         2-NO.sub.2      allyl                                                         2-NH.sub.2      allyl                                                         2-CF.sub.3 O    allyl                                                         2-CH.sub.3 O    allyl                                                         2-CH.sub.3 CH.sub.2 O                                                                         allyl                                                         2-CH.sub.3 S    allyl                                                         2-CH.sub.3 S(O) allyl                                                         2-CH.sub.3 SO.sub.2                                                                           allyl                                                         3-F             allyl                                                         3-Cl            allyl                                                         3-Br            allyl                                                         3-CN            allyl                                                         3-CH.sub.3      allyl                                                         3-CF.sub.3      allyl                                                         3-CH.sub.3 CH.sub.2                                                                           allyl                                                         3-OH            allyl                                                         3-NO.sub.2      allyl                                                         3-NH.sub.2      allyl                                                         3-CF.sub.3 O    allyl                                                         3-CH.sub.3 O    allyl                                                         3-CH.sub.3 CH.sub.2 O                                                                         allyl                                                         3-CH.sub.3 S    allyl                                                         3-CH.sub.3 S(O) allyl                                                         3-CH.sub.3 SO.sub.2                                                                           allyl                                                         4-F             allyl                                                         4-Cl            allyl                                                         4-Br            allyl                                                         4-CN            allyl                                                         4-CH.sub.3      allyl                                                         4-CF.sub.3      allyl                                                         4-CH.sub.3 CH.sub.2                                                                           allyl                                                         4-OH            allyl                                                         4-NO.sub.2      allyl                                                         4-NH.sub.2      allyl                                                         4-CF.sub.3 O    allyl                                                         4-CH.sub.3 O    allyl                                                         4-CH.sub.3 CH.sub.2 O                                                                         allyl                                                         4-CH.sub.3 S    allyl                                                         4-CH.sub.3 S(O) allyl                                                         4-CH.sub.3 SO.sub.2                                                                           allyl                                                         3,5-di-F        allyl                                                         3,5-di-Cl       allyl                                                         3,5-di-Br       allyl                                                         3,5-di-CH.sub.3 allyl                                                         3,5-di-CH.sub.3 CH.sub.2                                                                      allyl                                                         3,5-di-CH.sub.3 O                                                                             allyl                                                         3,5-di-CH.sub.3 CH.sub.2 O                                                                    allyl                                                         H               CH.sub.3 CH.sub.2 CH.sub.2                                    2-F             CH.sub.3 CH.sub.2 CH.sub.2                                    2-Cl            CH.sub.3 CH.sub.2 CH.sub.2                                    2-Br            CH.sub.3 CH.sub.2 CH.sub.2                                    2-CN            CH.sub.3 CH.sub.2 CH.sub.2                                    2-CH.sub.3      CH.sub.3 CH.sub.2 CH.sub.2                                    2-CF.sub.3      CH.sub.3 CH.sub.2 CH.sub.2                                    2-CH.sub.3 CH.sub.2                                                                           CH.sub.3 CH.sub.2 CH.sub.2                                    2-OH            CH.sub.3 CH.sub.2 CH.sub.2                                    2-NO.sub.2      CH.sub.3 CH.sub.2 CH.sub.2                                    2-NH.sub.2      CH.sub.3 CH.sub.2 CH.sub.2                                    2-CF.sub.3 O    CH.sub.3 CH.sub.2 CH.sub.2                                    2-CH.sub.3 O    CH.sub.3 CH.sub.2 CH.sub.2                                    2-CH.sub.3 CH.sub.2 O                                                                         CH.sub.3 CH.sub.2 CH.sub.2                                    2-CH.sub.3 S    CH.sub.3 CH.sub.2 CH.sub.2                                    2-CH.sub.3 S(O) CH.sub.3 CH.sub.2 CH.sub.2                                    2-CH.sub.3 SO.sub.2                                                                           CH.sub.3 CH.sub.2 CH.sub.2                                    3-F             CH.sub.3 CH.sub.2 CH.sub.2                                    3-Cl            CH.sub.3 CH.sub.2 CH.sub.2                                    3-Br            CH.sub.3 CH.sub.2 CH.sub.2                                    3-CN            CH.sub.3 CH.sub.2 CH.sub.2                                    3-CH.sub.3      CH.sub.3 CH.sub.2 CH.sub.2                                    3-CF.sub.3      CH.sub.3 CH.sub.2 CH.sub.2                                    3-CH.sub.3 CH.sub.2                                                                           CH.sub.3 CH.sub.2 CH.sub.2                                    3-OH            CH.sub.3 CH.sub.2 CH.sub.2                                    3-NO.sub.2      CH.sub.3 CH.sub.2 CH.sub.2                                    3-NH.sub.2      CH.sub.3 CH.sub.2 CH.sub.2                                    3-CF.sub.3 O    CH.sub.3 CH.sub.2 CH.sub.2                                    3-CH.sub.3 O    CH.sub.3 CH.sub.2 CH.sub.2                                    3-CH.sub.3 CH.sub.2 O                                                                         CH.sub.3 CH.sub.2 CH.sub.2                                    3-CH.sub.3 S    CH.sub.3 CH.sub.2 CH.sub.2                                    3-CH.sub.3 S(O) CH.sub.3 CH.sub.2 CH.sub.2                                    3-CH.sub.3 SO.sub.2                                                                           CH.sub.3 CH.sub.2 CH.sub.2                                    4-F             CH.sub.3 CH.sub.2 CH.sub.2                                    4-Cl            CH.sub.3 CH.sub.2 CH.sub.2                                    4-Br            CH.sub.3 CH.sub.2 CH.sub.2                                    4-CN            CH.sub.3 CH.sub.2 CH.sub.2                                    4-CH.sub.3      CH.sub.3 CH.sub.2 CH.sub.2                                    4-CF.sub.3      CH.sub.3 CH.sub.2 CH.sub.2                                    4-CH.sub.3 CH.sub.2                                                                           CH.sub.3 CH.sub.2 CH.sub.2                                    4-OH            CH.sub.3 CH.sub.2 CH.sub.2                                    4-NO.sub.2      CH.sub.3 CH.sub.2 CH.sub.2                                    4-NH.sub.2      CH.sub.3 CH.sub.2 CH.sub.2                                    4-CF.sub.3 O    CH.sub.3 CH.sub.2 CH.sub.2                                    4-CH.sub.3 O    CH.sub.3 CH.sub.2 CH.sub.2                                    4-CH.sub.3 CH.sub.2 O                                                                         CH.sub.3 CH.sub.2 CH.sub.2                                    4-CH.sub.3 S    CH.sub.3 CH.sub.2 CH.sub.2                                    4-CH.sub.3 S(O) CH.sub.3 CH.sub.2 CH.sub.2                                    4-CH.sub.3 SO.sub.2                                                                           CH.sub.3 CH.sub.2 CH.sub.2                                    3,5-di-F        CH.sub.3 CH.sub.2 CH.sub.2                                    3,5-di-Cl       CH.sub.3 CH.sub.2 CH.sub.2                                    3,5-di-Br       CH.sub.3 CH.sub.2 CH.sub.2                                    3,5-di-CH.sub.3 CH.sub.3 CH.sub.2 CH.sub.2                                    3,5-di-CH.sub.3 CH.sub.2                                                                      CH.sub.3 CH.sub.2 CH.sub.2                                    3,5-di-CH.sub.3 O                                                                             CH.sub.3 CH.sub.2 CH.sub.2                                    3,5-di-CH.sub.3 CH.sub.2 O                                                                    CH.sub.3 CH.sub.2 CH.sub.2                                    H               HOCH.sub.2 CH.sub.2                                           2-F             HOCH.sub.2 CH.sub.2                                           2-Cl            HOCH.sub.2 CH.sub.2                                           2-Br            HOCH.sub.2 CH.sub.2                                           2-CN            HOCH.sub.2 CH.sub.2                                           2-CH.sub.3      HOCH.sub.2 CH.sub.2                                           2-CF.sub.3      HOCH.sub.2 CH.sub.2                                           2-CH.sub.3 CH.sub.2                                                                           HOCH.sub.2 CH.sub.2                                           2-OH            HOCH.sub.2 CH.sub.2                                           2-NO.sub.2      HOCH.sub.2 CH.sub.2                                           2-NH.sub.2      HOCH.sub.2 CH.sub.2                                           2-CF.sub.3 O    HOCH.sub.2 CH.sub.2                                           2-CH.sub.3 O    HOCH.sub.2 CH.sub.2                                           2-CH.sub.3 CH.sub.2 O                                                                         HOCH.sub.2 CH.sub.2                                           2-CH.sub.3 S    HOCH.sub.2 CH.sub.2                                           2-CH.sub.3 S(O) HOCH.sub.2 CH.sub.2                                           2-CH.sub.3 SO.sub.2                                                                           HOCH.sub.2 CH.sub.2                                           3-F             HOCH.sub.2 CH.sub.2                                           3-Cl            HOCH.sub.2 CH.sub.2                                           3-Br            HOCH.sub.2 CH.sub.2                                           3-CN            HOCH.sub.2 CH.sub.2                                           3-CH.sub.3      HOCH.sub.2 CH.sub.2                                           3-CF.sub.3      HOCH.sub.2 CH.sub.2                                           3-CH.sub.3 CH.sub.2                                                                           HOCH.sub.2 CH.sub.2                                           3-OH            HOCH.sub.2 CH.sub.2                                           3-NO.sub.2      HOCH.sub.2 CH.sub.2                                           3-NH.sub.2      HOCH.sub.2 CH.sub.2                                           3-CF.sub.3 O    HOCH.sub.2 CH.sub.2                                           3-CH.sub.3 O    HOCH.sub.2 CH.sub.2                                           3-CH.sub.3 CH.sub.2 O                                                                         HOCH.sub.2 CH.sub.2                                           3-CH.sub.3 S    HOCH.sub.2 CH.sub.2                                           3-CH.sub.3 S(O) HOCH.sub.2 CH.sub.2                                           3-CH.sub.3 SO.sub.2                                                                           HOCH.sub.2 CH.sub.2                                           4-F             HOCH.sub.2 CH.sub.2                                           4-Cl            HOCH.sub.2 CH.sub.2                                           4-Br            HOCH.sub.2 CH.sub.2                                           4-CN            HOCH.sub.2 CH.sub.2                                           4-CH.sub.3      HOCH.sub.2 CH.sub.2                                           4-CF.sub.3      HOCH.sub.2 CH.sub.2                                           4-CH.sub.3 CH.sub.2                                                                           HOCH.sub.2 CH.sub.2                                           4-OH            HOCH.sub.2 CH.sub.2                                           4-NO.sub.2      HOCH.sub.2 CH.sub.2                                           4-NH.sub.2      HOCH.sub.2 CH.sub.2                                           4-CF.sub.3 O    HOCH.sub.2 CH.sub.2                                           4-CH.sub.3 O    HOCH.sub.2 CH.sub.2                                           4-CH.sub.3 CH.sub.2 O                                                                         HOCH.sub.2 CH.sub.2                                           4-CH.sub.3 S    HOCH.sub.2 CH.sub.2                                           4-CH.sub.3 S(O) HOCH.sub.2 CH.sub.2                                           4-CH.sub.3 SO.sub.2                                                                           HOCH.sub.2 CH.sub.2                                           3,5-di-F        HOCH.sub.2 CH.sub.2                                           3,5-di-Cl       HOCH.sub.2 CH.sub.2                                           3,5-di-Br       HOCH.sub.2 CH.sub.2                                           3,5-di-CH.sub.3 HOCH.sub.2 CH.sub.2                                           3,5-di-CH.sub.3 CH.sub.2                                                                      HOCH.sub.2 CH.sub.2                                           3,5-di-CH.sub.3 O                                                                             HOCH.sub.2 CH.sub.2                                           3,5-di-CH.sub.3 CH.sub.2 O                                                                    HOCH.sub.2 CH.sub.2                                           H               (CH.sub.3).sub.2 CH                                           2-F             (CH.sub.3).sub.2 CH                                           2-Cl            (CH.sub.3).sub.2 CH                                           2-Br            (CH.sub.3).sub.2 CH                                           2-CN            (CH.sub.3).sub.2 CH                                           2-CH.sub.3      (CH.sub.3).sub.2 CH                                           2-CF.sub.3      (CH.sub.3).sub.2 CH                                           2-CH.sub.3 CH.sub.2                                                                           (CH.sub.3).sub.2 CH                                           2-OH            (CH.sub.3).sub.2 CH                                           2-NO.sub.2      (CH.sub.3).sub.2 CH                                           2-NH.sub.2      (CH.sub.3).sub.2 CH                                           2-CF.sub.3 O    (CH.sub.3).sub.2 CH                                           2-CH.sub.3 O    (CH.sub.3).sub.2 CH                                           2-CH.sub.3 CH.sub.2 O                                                                         (CH.sub.3).sub.2 CH                                           2-CH.sub.3 S    (CH.sub.3).sub.2 CH                                           2-CH.sub.3 S(O) (CH.sub.3).sub.2 CH                                           2-CH.sub.3 SO.sub.2                                                                           (CH.sub.3).sub.2 CH                                           3-F                                                                           3-Cl            (CH.sub.3).sub.2 CH                                           3-Br            (CH.sub.3).sub.2 CH                                           3-CN            (CH.sub.3).sub.2 CH                                           3-CH.sub.3      (CH.sub.3).sub.2 CH                                           3-CF.sub.3      (CH.sub.3).sub.2 CH                                           3-CH.sub.3 CH.sub.2                                                                           (CH.sub.3).sub.2 CH                                           3-OH            (CH.sub.3).sub.2 CH                                           3-NO.sub.2      (CH.sub.3).sub.2 CH                                           3-NH.sub.2      (CH.sub.3).sub.2 CH                                           3-CF.sub.3 O    (CH.sub.3).sub.2 CH                                           3-CH.sub.3 O    (CH.sub.3).sub.2 CH                                           3-CH.sub.3 CH.sub.2 O                                                                         (CH.sub.3).sub.2 CH                                           3-CH.sub.3 S    (CH.sub.3).sub.2 CH                                           3-CH.sub.3 S(O) (CH.sub.3).sub.2 CH                                           3-CH.sub.3 SO.sub.2                                                                           (CH.sub.3).sub.2 CH                                           4-F             (CH.sub.3).sub.2 CH                                           4-Cl            (CH.sub.3).sub.2 CH                                           4-Br            (CH.sub.3).sub.2 CH                                           4-CN            (CH.sub.3).sub.2 CH                                           4-CH.sub.3      (CH.sub.3).sub.2 CH                                           4-CF.sub.3      (CH.sub.3).sub.2 CH                                           4-CH.sub.3 CH.sub.2                                                                           (CH.sub.3).sub.2 CH                                           4-OH            (CH.sub.3).sub.2 CH                                           4-NO.sub.2      (CH.sub.3).sub.2 CH                                           4-NH.sub.2      (CH.sub.3).sub.2 CH                                           4-CF.sub.3 O    (CH.sub.3).sub.2 CH                                           4-CH.sub.3 O    (CH.sub.3).sub.2 CH                                           4-CH.sub.3 CH.sub.2 O                                                                         (CH.sub.3).sub.2 CH                                           4-CH.sub.3 S    (CH.sub.3).sub.2 CH                                           4-CH.sub.3 S(O) (CH.sub.3).sub.2 CH                                           4-CH.sub.3 SO.sub.2                                                                           (CH.sub.3).sub.2 CH                                           3,5-di-F        (CH.sub.3).sub.2 CH                                           3,5-di-Cl       (CH.sub.3).sub.2 CH                                           3,5-di-Br       (CH.sub.3).sub.2 CH                                           3,5-di-CH.sub.3 (CH.sub.3).sub.2 CH                                           3,5-di-CH.sub.3 CH.sub.2                                                                      (CH.sub.3).sub.2 CH                                           3,5-di-CH.sub.3 O                                                                             (CH.sub.3).sub.2 CH                                           3,5-di-CH.sub.3 CH.sub.2 O                                                                    (CH.sub.3).sub.2 CH                                           ______________________________________                                    

Representative compounds of the present invention include the compoundsof Formula XI, XII, XIII or XIV: ##STR14## wherein R¹⁶ is H, methyl,ethyl, allyl or benzyl, R³ is H or OH, R² is H, CH₃, CH₃ CH₂, allyl, CH₃CH₂ CH₂, HOCH₂ CH₂ CH₂, or (CH₃)₂ CH and R¹⁹ is selected from thefollowing group of substituents: ##STR15##

Representative compounds of the present invention include the compoundsidentified as follows:

17-Ethyl-1,14-dihydroxy-12-2'-(4"-phenyloxy-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(3"-phenyloxy-4"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-phenyloxy-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(4'"-fluorophenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(4'"-chlorophenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(4'"-methylphenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(3"-(4'"-methylphenyloxy)-4"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(4'"-methylphenyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(4'"-phenoxyphenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(4'"-phenoxyphenyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(3"-(4'"-phenoxyphenyloxy)-4"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(naphth-1-yloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(3"-(naphth-1-yloxy)-4"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(naphth-1-yl-oxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(naphth-2-yloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(naphth-2-yloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(3"-(naphth-2-yloxy)-4"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-2'-(4"-(naphth-2-yloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(6'"-methoxy-naphth-2-yloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(3"-(6'"-methoxy-naphth-2-yloxy)-4"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo 22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(6'"-methoxy-naphth-2-yloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(3"-(4'"-methoxyphenyloxy)-4"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(4'"-methoxyphenyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(3"-(3'"-methoxyphenyloxy)-4"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(3'"-methoxyphenyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(3"-(4'"-hydroxyphenyloxy)-4"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(4'"-hydroxyphenyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(6'"-hydroxynaphth-2-yloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(3"-(6'"-hydroxynaphth-2-yloxy)-4"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(3'",4'"-dichlorophenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(phenanthr-9-yl-oxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(3'",4'"-methylenedioxy-phenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(2'",3'"-dihydrobenzofuran-5-yloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Allyl-1,14-dihydroxy-12-2'-(4"-(naphth-2-yloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(1'",4'"-benzodioxane-6-yloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,-10,16-tetraone;

17-Ethyl-1,2,14-trihydroxy-12-2'-(4"-(naphth-2-yl-oxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-3,10,16-trione;

17-Ethyl-1-hydroxy-12-2'-(4"-(4'"-dimethylamino)-phenyloxy-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !-octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-2'-(4"-hydroxy-3"-(4'"-dimethylamino)phenyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !-octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-allyloxy-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-butynyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-cinnamyloxy-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(3"-methoxy-4"-phenylpropyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-allyloxy-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(3"-allyloxy-4"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(3"-hydroxy-4"-isopropyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-hydroxy-3"-isopropyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-sec-butenyloxy-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(3"-sec-butenyloxy-4"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(trans-2'"-butenyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(3"-(trans-2'"-butenyloxy)-4"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(3"-hydroxy-4"-(3'"-methyl-2-butenyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-hydroxy-3"-(3'"-methyl-2-butenyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(3"-hydroxy-4"-(2'"-methylpropenyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-hydroxy-3"-(2'"-methylpropenyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-cinnamyloxy-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(3"-cinnamyloxy-4"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-2'-(4"-sec-butenyloxy-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-2'-(3"-sec-butenyloxy-4"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-2'-(4"-cinnamyloxy-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-2'-(3"-methoxy-4"-phenylpropyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9!octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(4'"-methoxyphenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(3'"-methoxyphenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(6'"-hydroxy-naphth-2-yloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(4'"-hydroxyphenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(4'"-methylthiophenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-methylphenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(3'"-methylphenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(3'",4'"-dimethylphenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-2'-(4"-allyloxy-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-2'-(4"-(2'"-butynyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-2'-(4"-cinnamyloxy-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-2'-(3"-methoxy-4"-phenylpropyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9!octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl -1-hydroxy-12- 2'-(4"-allyloxy-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-2'-(3"-allyloxy-4"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-2'-(3"-hydroxy-4"-isopropyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo 22.3.1.0⁴,9!-octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-2'-(4"-hydroxy-3"-isopropyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !-octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-2'-(4"-(trans-2'"-butenyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-2'-(3"-(trans-2'"-butenyloxy)-4"-hydroxycyclohexyl)-1'-methylvinyl!23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-2'-(3"-hydroxy-4"-(3'"methyl-2-butenyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-2'-(4"-hydroxy-3"-(3'"-methyl-2-butenyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-2'-(3"-hydroxy-4"-(2'"-methylpropenyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-2'-(4"-hydroxy-3"-(2'"-methylpropenyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-2'-(3"-cinnamyloxy-4"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-sec-phenethyloxy-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-methylcinnamyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(4'"-methyl-2'",4'"-hexadieny-oxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,-10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(p-methoxycinnamyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(3'",4'"-methylenedioxycinnamyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(4'",4'"-dimethyl-2'"-transpentenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

-Ethyl-1,14-dihydroxy-12-2'-(4"-(3'"-cyclohexyl-2'"-transpropenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-p-fluorocinnamyloxy-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-p-chlorocinnamyloxy-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-p-bromocinnamyloxy-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(3"-methoxy-4"-p-fluorophenylpropyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-2'-(3",4"-diallyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0.sup.4,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-2'-(3",4"-dipropyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0.sup.4,9 !-octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-benzylamino)-ethoxy-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-2'-(4"-(2'"-benzylamino)ethoxy-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-benzyloxyethoxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-benzyloxymethoxy-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(napth-2-yloxy)-3"-allyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(ethoxycarbomethoxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(p-hydroxycinnamyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-2'-(4"-(p-hydroxycinnamyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-phenyl-2'"-oxo-ethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-2'-(4"-(2'"-phenyl-2'"-oxo-ethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-phenyl-2'"-oxo-ethyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3""-methoxyphenyl)-2'"-oxo-ethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-2'-(4"-(2'"-(3""-methoxyphenyl)-2'"-oxo-ethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12- 2'-(4"-(2'"-(3""-methoxyphenyl)-2'"-oxo-ethyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(4""-methoxyphenyl)-2'"-oxo-ethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-2'-(4"-(2'"-(4""-methoxyphenyl)-2'"-oxo-ethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(4""-methoxyphenyl)-2'"-oxo-ethyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3"",5""-dimethoxyphenyl)-2'"-oxo-ethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-2'-(4"-(2'"-(3"",5""-dimethoxyphenyl)-2'"-oxo-ethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3"",5""-dimethoxyphenyl)-2'"-oxo-ethyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4'-(2'"-(3"",5""-difluorophenyl)-2'"-oxo-ethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-2'-(4"-(2"-(3"",5""-difluorophenyl-2'"-oxo-ethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3"",5""-difluorophenyl)-2'"-oxo-ethyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(2'-(4""-hydroxyphenyl)-2'"-oxo-ethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-2'-(4"-(2'"-(4""-hydroxyphenyl)-2'"-oxo-ethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(4""-hydroxyphenyl)-2'"-oxo-ethyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-phenyl-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-2'-(4"-(2'"-phenyl-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-phenyl-2'"-hydroxyethyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3""-methoxyphenyl)-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-2'-(4"-(2'"-(3""-methoxyphenyl)-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3""-methoxyphenyl)-2'"-hydroxyethyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3"",5""-dimethoxyphenyl)-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-2'-(4"-(2'"-(3"",5""-dimethoxyphenyl)-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3"",5""-dimethoxyphenyl)-2'"-hydroxyethyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3"",5""-difluorophenyl)-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-2'-(4"-(2'"-(3"",5""-difluorophenyl-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3"",5""-difluorophenyl)-2'"-hydroxyethyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(4""-hydroxyphenyl)-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-2'-(4"-(2'"-(4""-hydroxyphenyl)-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(4""-hydroxyphenyl)-2'"-hydroxyethyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(m-fluorocinnamyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(3'",5""-difluorocinnamyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(m-nitrocinnamyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(3'"-phenyl-2'"-propynyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-phenyl-2'"-propenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(p-hydroxycinnamyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(p-hydroxyphenpropyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(m-hydroxycinnamyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(m-hydroxymethylbenzyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(m-hydroxycinnamyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(3'",5""-difluorocinnamyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(p-carboxybenzyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(m-carboxybenzyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(m-carbomethoxybenzyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,-25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(m-isopropylcarboxamidobenzyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(m-butylcarboxamidobenzyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-acetamidoxy-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-carboxymethoxy-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22-3.1.13⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(N-phenylacetamidoxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(N-benzylacetamidoxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-2'-(4"-carboxymethoxy-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-2'-(4"-(N-benzylamidoxymethoxy-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-2'-(4"-(N-methyltyrosine)amidoxy-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(m-methylphenyl)-2'"-oxo-ethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(p-methylphenyl)-2'"-oxo-ethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(m-methylphenyl)-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(m-ethylphenyl)-2'"-oxo-ethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-phenylethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-phenyl-2'"-acetoxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-morpholinoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(naphth-2-ylmethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(4'",5'"-methylenedioxy-benzyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(4'"-N,N,-dimethylaminophenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(3'"-fluorophenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(3'"-(2""-dioxolanylphenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(3'"-formylphenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(3'"-carboxyphenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(3'",4'"-dimethoxyphenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(4'"-trifluoromethylphenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(3'",5'"-bis(trifluoromethyl)phenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-2'-(4"-(4'"-methylphenyloxy)-3"-hydroxy-cyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-2'-(4"-hydroxy-3"-(4'"-methylphenyloxy)-cyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-2'-(4"-(4'"-hydroxyphenyloxy)-3"-hydroxy-cyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-2'-(4"-hydroxy-3"-(4'"-hydroxyphenyl-oxy)cyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-2'-(4"-(4'"-hydroxymethylphenyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetra-methyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !-octacos-18-ene-2,3,10,16-tetraone and;

17-Ethyl-1-hydroxy-12-2'-(4"-hydroxy-3"-(4'"-hydroxymethyl-phenyloxy)cyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-2'-(4"-hydroxy-3"-(4'"-formylphenyloxy)-cyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-2'-(4"-(4'"-N,N-dimethylaminophenyloxy)-3"-hydroxycyclohexyl)-1'-methyl-vinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-2'-(4"-hydroxy-3"-(4'"-N,N-dimethylaminophenyloxy)cyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-2'-(4"-phenyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy -12- 2'-(4"-hydroxy-3"-phenyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-2'-(4"-(4'"-methoxyphenyloxy)-3"-hydroxy-cyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone and;

17-Ethyl-1-hydroxy-12-2'-(4"-hydroxy-3"-(4'"-methoxyphenyloxy)-cyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-2'-(4"-(3'"-methoxyphenyloxy)-3"-hydroxy-cyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-2'-(4"-hydroxy-3"-(3'"-methoxyphenyloxy)-cyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-p-t-butylphenyl-2'"-oxoethyl-oxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-m-nitrophenyl-2'"-oxoethyl-oxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy -12- 2'-(4"-(2'"-m-isopropoxyphenyl-2'"-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0.sup.4,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-m-bromophenyl-2'"-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-m-fluorophenyl-2'"-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-m-chloromethylphenyl-2'"-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-m-cyanophenyl-2'"-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-m,m-difluorophenyl-2'"-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-m,m-dimethylphenyl-2'"-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-m-chlorophenyl-2'"-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12- 2'-(4"-(2'"-m-trifluoromethylphenyl-2'"-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(2-naphthyl)-2'"-oxoethyl-oxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-m-fluorophenyl-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-m-chloromethylphenyl-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-m,m-dimethylphenyl-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-m-chlorophenyl-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12- 2'-(4"-(2'"-m-trifluoromethylphenyl-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(2-naphthyl)-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-phenyl-2'"-benzyloxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatri-cyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-phenyl-2'"-allyloxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-phenyl-2'"-methoxy-ethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !-octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-phenyl-2'"-aminoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-phenyl-2'"-oxoethyloxy)-3"-allyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-phenyl-2'"-oxoethyloxy)-3"-propyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-phenyl-2'"-oxoethyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(m-fluorophenyl-2'"-oxoethyloxy)-3"-isopropoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(m-fluorophenyl-2'"-oxoethyloxy)-3"-allyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(m-fluorophenyl-2'"-oxoethyloxy)-3"-propyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(m-fluorophenyl-2'"-oxoethyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(m-methylphenyl-2'"-oxoethyloxy)-3"-isopropoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(m-methylphenyl-2'"-oxoethyloxy)-3"-allyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(m-methylphenyl-2'"-oxoethyloxy)-3'-propyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(m-methylphenyl-2'"-oxoethyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(m-methoxyphenyl-2'"-oxoethyloxy)-3"-isopropoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(m-methoxyphenyl-2'"-oxoethyloxy)-3"-allyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(m-methoxyphenyl-2'"-oxoethyloxy)-3"-propyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(m-methoxyphenyl-2'"-oxoethyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1-hydroxy-12-2'-(4"-(2'"-phenyl-2'"-oxoethyloxy)-3"-isopropoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1-hydroxy-12-2'-(4"-(2'"-phenyl-2'"-oxoethyloxy)-3"-allyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1-hydroxy-12-2'-(4"-(2'"-phenyl-2'"-oxoethyloxy)-3"-propyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1-hydroxy-12-2'-(4"-(2'"-phenyl-2'"-oxoethyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1-hydroxy-12-2'-(4"-(2'"-(m-fluorophenyl-2'"-oxoethyloxy)-3"-isopropoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1-hydroxy-12-2'-(4"-(2'"-(m-fluorophenyl-2'"-oxoethyloxy)-3"-allyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1-hydroxy-12-2'-(4"-(2'"-(m-fluorophenyl-2'"-oxoethyloxy)-3"-propyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1-hydroxy-12-2'-(4"-(2'"-(m-fluorophenyl-2'"-oxoethyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1-hydroxy-12-2'-(4"-(2'"-(m-methylphenyl-2'"-oxoethyloxy)-3"-isopropoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1-hydroxy-12-2'-(4"-(2'"-(m-methylphenyl-2'"-oxoethyloxy)-3"-allyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1-hydroxy-12-2'-(4"-(2'"-(m-methylphenyl-2'"-oxoethyloxy)-3"-propyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1-hydroxy-12-2'-(4"-(2'"-(m-methylphenyl-2'"-oxoethyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1-hydroxy-12-2'-(4"-(2'"-(m-methoxyphenyl-2'"-oxoethyloxy)-3"-isopropoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1-hydroxy-12-2'-(4"-(2'"-(m-methoxyphenyl-2'"-oxoethyloxy)-3"-allyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1-hydroxy-12-2'-(4"-(2'"-(m-methoxyphenyl-2'"-oxoethyloxy)-3"-propyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1-hydroxy-12-2'-(4"-(2'"-(m-methoxyphenyl-2'"-oxoethyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1-hydroxy-12-2'-(4"-(2'"-(3"",5""-dimethoxyphenyl-2'"-oxoethyloxy)-3"-isopropoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.04 ,9!octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1-hydroxy-12-2'-(4"-(2'"-(3"",5""-dimethoxyphenyl-2'"-oxoethyloxy)-3"-allyloxycyclohexyl)-1"-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1-hydroxy-12-2'-(4"-(2'"-(3"",5""-dimethoxyphenyl-2'"-oxoethyloxy)-3"-propyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1-hydroxy-12-2'-(4"-(2'"-(3"",5""-dimethoxyphenyl-2'"-oxoethyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1-hydroxy-12-2'-(4"-(2'"-(3"",5""-dimethoxyphenyl-2'"-hydroxyethyloxy)-3"-isopropoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1-hydroxy-12-2'-(4"-(2'"-(3"",5""-dimethoxyphenyl-2'"-hydroxyethyloxy)-3"-allyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1-hydroxy-12-2'-(4"-(2'"-(3"",5""-dimethoxyphenyl-2'"-hydroxyethyloxy)-3"-propyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1-hydroxy-12- 2'-(4"-(2'"-(3"",5""-dimethoxyphenyl-2'"-hydroxyethyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3"",5""-dimethoxyphenyl-2'"-oxoethyloxy)-3"-isopropoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3"",5""-dimethoxyphenyl-2'"-oxoethyloxy)-3"-allyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3"",5""-dimethoxyphenyl-2'"-oxoethyloxy)-3"-propyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3"",5""-dimethoxyphenyl-2'"-oxoethyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3"",5""-dimethoxyphenyl-2'"-hydroxyethyloxy)-3"-isopropoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3"",5""-dimethoxyphenyl-2'"-hydroxyethyloxy)-3"-allyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3"",5""-dimethoxyphenyl-2'"-hydroxyethyloxy)-3"-propyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3"",5""-dimethoxyphenyl-2'"-hydroxyethyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1-hydroxy-12-2'-(4"-(2'"-(3"",5""-dimethylphenyl-2'"-oxoethyloxy)-3"-isopropoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1-hydroxy-12-2'-(4"-(2'"-(3"",5""-dimethylphenyl-2'"-oxoethyloxy)-3"-allyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1-hydroxy-12-2'-(4"-(2'"-(3"",5""-dimethylphenyl-2'"-oxoethyloxy)-3"-propyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1-hydroxy-12-2'-(4"-(2'"-(3"",5""-dimethylphenyl-2'"-oxoethyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1-hydroxy-12-2'-(4"-(2'"-(3"",5""-dimethylphenyl-2'"-hydroxyethyloxy)-3"-isopropoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1-hydroxy-12-2'-(4"-(2'"-(3"",5""-dimethylphenyl-2'"-hydroxyethyloxy)-3"-allyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1-hydroxy-12-2'-(4"-(2'"-(3"",5""-dimethylphenyl-2'"-hydroxyethyloxy)-3"-propyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1-hydroxy-12-2'-(4"-(2'"-(3"",5""-dimethylphenyl-2'"-hydroxyethyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3"",5""-dimethylphenyl-2'"-oxoethyloxy)-3"-isopropoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3"",5""-dimethylphenyl-2'"-oxoethyloxy)-3"-allyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3"",5""-dimethylphenyl-2'"-oxoethyloxy)-3"-propyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3"",5""-dimethylphenyl-2'"-oxoethyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3"",5""-dimethylphenyl-2'"-hydroxyethyloxy)-3"-isopropoxycyclohexyl)-1"-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12- 2'-(4"-(2'41-(3"",5""-dimethylphenyl-2'"-hydroxyethyloxy)-3"-allyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3"",5""-dimethylphenyl-2'"-hydroxyethyloxy)-3"-propyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3"",5""-dimethylphenyl-2'"-hydroxyethyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-phenyl-2'"-hydroxyethyloxy)-3"-isopropoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-phenyl-2'"-hydroxyethyloxy)-3"-allyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-phenyl-2'"-hydroxyethyloxy)-3"-propyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-phenyl-2'"-hydroxyethyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(m-fluorophenyl-2'"-hydroxyethyloxy)-3"-isopropoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(m-fluorophenyl-2'"-hydroxyethyloxy)-3"-allyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(m-fluorophenyl-2'"-hydroxyethyloxy)-3"-propyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.00,9!octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(m-fluorophenyl-2'"-hydroxyethyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(m-methylphenyl-2'"-hydroxyethyloxy)-3"-isopropoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(m-methylphenyl-2'"-hydroxyethyloxy)-3"-allyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(m-methylphenyl-2'"-hydroxyethyloxy)-3"-propyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(m-methylphenyl-2'"-hydroxyethyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(m-methoxyphenyl-2'"-hydroxyethyloxy)-3"-isopropoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(m-methoxyphenyl-2'"-hydroxyethyloxy)-3"-allyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(m-methoxyphenyl-2'"-hydroxyethyloxy)-3"-propyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(m-methoxyphenyl-2'"-hydroxyethyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1-hydroxy-12-2'-(4"-(2'"-phenyl-2'"-hydroxyethyloxy)-3"-isopropoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1-hydroxy-12-2'-(4"-(2'"-phenyl-2'"-hydroxyethyloxy)-3"-allyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1-hydroxy-12-2'-(4"-(2'"-phenyl-2'"-hydroxyethyloxy)-3"-propyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1-hydroxy-12-2'-(4"-(2'"-phenyl-2'"-hydroxyethyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1-hydroxy-12-2'-(4"-(2'"-(m-fluorophenyl-2'"-hydroxyethyloxy)-3"-isopropoxycyclohexyl)-1"-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1-hydroxy-12-2'-(4"-(2'"-(m-fluorophenyl-2'"-hydroxyethyloxy)-3"-allyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1-hydroxy-12-2'-(4"-(2'"-(m-fluorophenyl-2'"-hydroxy-ethyloxy)-3"-propyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1-hydroxy-12-2'-(4"-(2'"-(m-fluorophenyl-2'"-hydroxy-ethyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1-hydroxy-12-2'-(4"-(2'"-(m-methylphenyl-2'"-hydroxy-ethyloxy)-3"-isopropoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1-hydroxy-12-2'-(4"-(2'"-(m-methylphenyl-2'"-hydroxy-ethyloxy)-3"-allyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1-hydroxy-12-2'-(4"-(2'"-(m-methylphenyl-2'"-hydroxy-ethyloxy)-3"-propyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1-hydroxy-12-2'-(4"-(2'"-(m-methylphenyl-2'"-hydroxy-ethyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1-hydroxy-12-2'-(4"-(2'"-(m-methoxyphenyl-2'"-hydroxy-ethyloxy)-3"-isopropoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1-hydroxy-12-2'-(4"-(2'"-(m-methoxyphenyl-2'"-hydroxy-ethyloxy)-3"-allyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1-hydroxy-12-2'-(4"-(2'"-(m-methoxyphenyl-2'"-hydroxy-ethyloxy)-3"-propyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1-hydroxy-12-2'-(4"-(2'"-(m-methoxyphenyl-2'"-hydroxy-ethyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-m,m-dichlorophenyl-2'"-oxo-ethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-m,m-dichlorophenyl-2'"-hydroxy-ethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-m,m-bistrifluoromethoxyphenyl-2'"-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-m,m-bistrifluoromethoxyphenyl-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-m,m-bistrifluoromethylphenyl-2'"-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-m,m-bistrifluoromethylphenyl-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-m,m-dihydroxyphenyl-2'"-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-m,m-dihydroxyphenyl-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3"",4"",5""-trimethyl)phenyl-2'"-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3"",4"",5""-trimethyl)phenyl-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3"",5""-dimethyl-4""-methoxy)-phenyl-2'"-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3"",5""-dimethyl-4""-methoxy)-phenyl-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3"",5""-dimethoxy-4""-methyl)-phenyl-2'"-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3"",5""-dimethoxy-4""-methyl)-phenyl-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3"",5""-difluoro-4""-methyl)-phenyl-2'"-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3"",5""-difluoro-4""-methyl)-phenyl-1-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3"",5""-dimethyl-4""-fluoro)-phenyl-2'"-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3"",5""-dimethyl-4""-fluoro)-phenyl-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3"",5""-dichloro-4""-methyl)-phenyl-2'"-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3"",5""-dichloro-4""-methyl)-phenyl-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3"",5""-dimethyl-4""-chloro)phenyl-2'"-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3"",5""-dimethyl-4""-chloro)phenyl-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3"",5""-bistrifluoromethoxy-4""-methyl)phenyl-2'"-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3"",5""-bistrifluoromethoxy-4""-methyl)phenyl-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0.sup.4,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3"",5""-dimethyl-4""-trifluoromethoxy)phenyl-2'"-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3"",5""-dimethyl-4""-trifluoromethoxy)phenyl-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3"",5""-dimethyl-4""-hydroxy)phenyl-2'"-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3"",5|"-dimethyl-4""-hydroxy)phenyl-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3"",5""-dihydroxy-4""-methyl)phenyl-2'"-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3"",5""-dihydroxy-4""-methyl)phenyl-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-m-thiomethylphenyl-2'"-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-m-thiomethylphenyl-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-m,m-bis(thiomethyl)phenyl-2'"-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-m,m-bis(thiomethyl)phenyl-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3"",5""-bis(thiomethyl)-4""-methyl)phenyl-2'"-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3"",5""-bis(thiomethyl)-4""-methyl)phenyl-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3""-chloro-5""-methyl)phenyl-2'"-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3""-chloro-5""-methyl)phenyl-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3""-chloro-5""-fluoro)phenyl-2'"-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3""-chloro-5""-fluoro)phenyl-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3""-chloro-5""-methoxy)phenyl-2'"-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3""-chloro-5""-methoxy)phenyl-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3""-chloro-5""-trifluoro-methyl)phenyl-2'"-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3""-chloro-5""-trifluoro-methyl)phenyl-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3""-chloro-5""-trifluoro-methoxy)phenyl-2'"-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3""-chloro-5""-trifluoro-methoxy)phenyl-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3""-fluoro-5""-methyl)phenyl-2'"-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3""-fluoro-5""-methyl)phenyl-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3""-fluoro-5""-methoxy)phenyl-2'"-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3""-fluoro-5""-methoxy)phenyl-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3""-fluoro-5""-trifluoro-methyl)phenyl-2'"-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3""-fluoro-5""-trifluoromethyl)phenyl-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone; p017-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3""-fluoro-5""-trifluoro-methoxy)phenyl-2'"-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3""-fluoro-5""-trifluoro-methoxy)phenyl-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3""-methyl-5""-methoxy)phenyl-2'"-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3""-methyl-5""-methoxy)phenyl-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3""-methyl-5""-trifluoro-methyl)phenyl-2'"-oxoethyloxy)-3"-methoxycyclohexyl)-1"-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3""-methyl-5""-trifluoro-methyl)phenyl-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(3",4"-di-(2'"-phenyl-2'"-oxo-ethyloxy)-cyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

17-ethyl-1,14-dihydroxy-12-2'-(3",4"-di-(2'"-phenyl-2'"-hydroxyethyloxy)-cyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;

or a pharmaceutically acceptable salt thereof.

B. Preparation of Compounds Within the Scope of the Present Invention

The starting materials for the preparation of the compounds of thisinvention are represented by Formula II: ##STR16## wherein: Q ishydrogen or methyl;

W is or (H, OH);

R³ is hydrogen, hydroxy, or C₁ -C₆ alkoxy;

R⁴ is hydrogen, or R³ and R⁴ taken together form a double bond;

R⁵ is methyl, ethyl, propyl or allyl; and

n is 1 or 2.

The production and characterization of compounds of Formula II is wellknown in the literature (see U.S. Pat. No. 4,894,366 issued Jan. 16,1990; U.S. Pat. No. 4,929,611 issued May 29, 1990; U.S. Pat. No.3,244,592 issued Apr. 15, 1966; EPO Publication No. 0,323,042; EPOPublication No. 0,356,399; PBJ Disclosure 63-17884; J. Am. Chem. Soc.,1987, 109, 5031; and J. Antibiotics, 1987, 40, 1249). Both biologicalfermentation and synthetic processes may be found. A synthetic route tocompounds of Formula II can involve modifications of a route describedin J. Am. Chem Soc., 1989, 111, 1157.

Biological fermentation followed by synthetic modification is presentlyfavored in the art as the method to produce compounds of Formula II.Organisms belonging to the genus Streptomyces such as Streptomycestsukubaensis, No. 9993 and Streptomyces hygroscopicus, No. 7238 placedin an aqueous nutrient medium will produce desired compounds in isolableamounts. The nutrient medium contains sources of assimilable carbon andnitrogen, preferably under aerobic conditions. Produced in fermentationare four compounds of Formula II, (A) where Q is methyl, W is O, R³ ishydroxyl, R⁴ is hydrogen, R⁵ is allyl and n is 2; (B) where Q is methyl,W is O, R³ is hydroxyl, R⁴ is hydrogen, R⁵ is ethyl and n is 2; (C)where Q is methyl, W is O, R³ is hydroxyl, R⁴ is hydrogen, R⁵ is methyland n is 2; and (D) where Q is methyl W is O, R³ is hydroxyl, R⁴ ishydrogen, R⁵ is allyl and n is 1.

A lyophilized sample of the isolated Streptomyces tsukubaensis, No. 9993was deposited with the Fermentation Research Institute, Agency ofIndustrial Science and Technology (No. 1-3, Higashi 1-chome, YatabemachiTsukuba-gun, Ibaraki Prefecture, Japan) under the deposit number of FERMP-7886 (deposit date: Oct. 5th, 1984), and then converted to BudapestTreaty route of the same depository on Oct. 19, 1985 under the newdeposit number of FERM BP-927.

Using the four compounds produced in fermentation above, the remainingcompounds of Formula II may be easily produced. The allyl of R⁵ may beconveniently reduced to propyl by well known methods, for example asdescribed in U.S. Pat. No. 4,894,366. The hydroxy of R³ may be protectedby well known methods, for example as disclosed in EPO Publication No.0,323,042. Likewise, the hydroxy at C-4" may also be protected. Inaddition, the hydroxy of R³ may be reduced to a hydrogen or eliminatedto form a double bond with R⁴ (by methods disclosed in U.S. Pat. No.4,894,366 or EPO Publication No. 0,323,042 or EPO Publication No.0,413,532). The carbonyl of W may be reduced to the alcohol by methodsdisclosed in EPO Publication No. 0,323,042 or by methods disclosed inU.S. Pat. No. 5,064,835 or in EPO Publication No. 0,445,975.

The methyl of Q as produced may be replaced with hydrogen ordemethylated and subsequently protected as desired, if necessary. Thisdemethylation of compounds wherein Q is methyl may be carried out in afermentation reaction using the compounds of Formula II as a feedstock.For instance, compound A named under Formula II above may bedemethylated at Q above by using the microorganism Actinomycetales ATCCNo. 53771 (described in U.S. Pat. No. 4,981,792, issued Jan. 1, 1991) orby using the microorganism Streptomyces tsukubaensis, No. 9993(described in EPO Publication No. 0,353,678). Similarly, Compound Bnamed under Formula II above may be demethylated at Q above using themicroorganism Actinoplanacete sp. ATCC No. 53771 (described in EPOPublication No. 0,349,061). In addition the compound of Formula IIwherein Q is H, W is O, R³ is hydroxy, R⁴ is hydrogen, R⁵ is ethyl and nis 2 may be produced directly by fermentation using the mutantmicroorganism Streptomyces hygroscipicus sup. ascomyceticus, No. 53855(being a blocked mutant of Streptomyces hygroscipicus sup.ascomyceticus, No. 14891) (as described in EPO Publications 0,388,152)Similarly, the compound of Formula II wherein Q is hydrogen, W is O, R³is hydroxy, R⁴ is hydrogen, R⁵ is methyl and n is 2 may be produceddirectly by fermentation using the mutant microorganism Streptomyceshygroscopicus sup. ascomyceticus, No. 53855 (being a blocked mutant ofStreptomyces hygroscopicus sup. ascomyceticus, No. 14891) (as describedin EPO Publication 0,388,153). Also, the compound of Formula II whereinQ is hydrogen, R³ is hydroxy, R⁴ is hydrogen, R⁵ is allyl, W is O and nis 2 and the compound of Formula II wherein the C-3" position is oxo(keto), R³ is hydroxy, R⁴ is hydrogen, R⁵ is allyl, W is O and n is 2may be produced directly by fermentation using the microorganismStreptomyces tsukubaensis, No. 9993 (described in EPO Publication No.0,353,678). The hydroxy of C-3" may be protected by methods similar tothose known for the protection of the hydroxyl groups of R³ and/or C-4",for example as disclosed in U.S. Pat. No. 4,894,366.

Suitable protecting groups for hydroxyl include those groups well knownin the art such as:

1-(lower alkylthio)(lower)alkyl, wherein "lower alkyl" indicates astraight, cyclic or branched chain of one to six carbon atoms, such aslower alkylthiomethyl (e.g. methylthiomethyl, ethylthiomethyl,propylthiomethyl, isopropylthiomethyl, butylthiomethyl,isobutylthiomethyl, hexylthiomethyl, etc.), and the like, in which thepreferred one may be C₁ -C₄ alkylthiomethyl and the most preferred onemay be methylthiomethyl; trisubstituted silyl such astri(lower)alkylsilyl (e.g. trimethylsilyl, triethylsilyl, tributysilyl,tri-i-propylsilyl, t-butyldimethylsilyl, tri-t-butylsilyl, etc.), loweralkyldiarylsilyl (e.g. methyl-diphenylsilyl, ethyl-diphenylsilyl,propyl-diphenylsilyl, t-butyldiphenylsilyl, etc.), and the like, inwhich the preferred one may be tri(C₁ -C₄)alkylsilyl and C₁ -C₄alkyl-diphenylsilyl, and the most preferred one may betert-butyl-dimethylsilyl, tri-i-propylsilyl andtert-butyl-diphenylsilyl; acyl such as aliphatic acyl, aromatic acyl andaliphatic acyl substituted with aromatic group, which are derived fromcarboxylic acids; and the like.

Compounds A, B, C and D of Formula II, organisms to produce the same,conditions of fermentation, separation techniques, and chemicalmodification of the products are fully described in U. S. Pat. No.4,894,366, issued Jan. 16, 1990 and U.S. Pat. No. 4,929,611, issued May29, 1990.

The 5α-reductase inhibitor may be an inhibitor of 5α-reductase isozyme 1and/or 5α-reductase isozyme 2. A preferred 5α-reductase inhibitor isfinasteride. It is also preferred that the 5α-reductase inhibitor beselective for the scalp-associated enzyme 5α-reductase isozyme 1.

4-Aza steroid compounds are known in the art as 5α-reductase inhibitors.For example, See U.S. Pat. Nos. 2,227,876, 3,239,417, 3,264,301 and3,285,918; French Patent No. 1,465,544; Doorenbos and Solomons, J.Pharm. Sci., 62, 4, pp. 638-640 (1973); Doorenbos and Brown, J. Pharm.Sci., 60, 8, pp. 1234-1235 (1971); and Doorenbos and Kim, J. Pharm.Sci., 63, 4, pp. 620-622 (1974).

In addition, U.S. Pat. Nos. 4,377,584, 4,220,775, 4,859,681, 4,760,071and the articles J. Med. Chem. 27, p. 1690-1701 (1984) and J. Med.Chem., 29, 29985-2315 (1986) of Rasmusson, et al., U.S. Pat. No.4,845,104 to Carlin, et al., and U.S. Pat. No. 4,732,897 to Cainelli, etat., described 4-aza 17β-substituted-5α-androstan-3-ones useful in thetreatment of DHT-related hyperandrogenic conditions.

Cyclosporin may be prepared essentially as described in U.S. Pat. No.4,117,118 or by R. Wenger, Transplant. Proc., 15 (4), Suppl. 1, 2230(1983) and is available from Sandoz Pharmaceuticals, East Hanover, N.J.

The potassium channel opener may be minoxidil, cromakalim, pinacidil, atriazine compound, a thiane-1-oxide, or other compounds.

Chemically minoxidil is6-amino-1,2-dihydro-hydroxy-2-imino-4-piperidinopyrimidine and analogsthereof. The preparation of these compounds are described in U.S. Pat.Nos. 3,382,247, 3,461,461 and 3,644,364 and J. M. McCall, et al., J.Org. Chem., 40, 3304 (1975). Related compounds are sulfoxypyrimidinium,-pyridinium, and -triazinium which are described in U.S. Pat. No.4,287,338. The term "minoxidil" includes any of the various forms of6-amino-1,2-dihydrohydroxy-2-imino-4-piperidinopyrimidine, derivativesand analogs thereof. Minoxidil is distributed by The Upjohn Company,Kalamazoo, Mich.

Chemically cromakalim is (3S-trans)3,4-dihydro-3-hydroxy-2,2-dimethyl-4-(2-oxo-1-pyrrolidinyl)-2H-1-benxopyran-6-carbonitrile.Cromakalim is distributed by SmithKline Consumer Products, Philadelphia,Pa.

Pinacidil is chemically,N-cyano-N'-4-pyridinyl-N"-(1,2,2-trimethylpropyl)-guanidine monohydrate.The preparation of pinacidil is described in U.S. Pat. No. 4,057,636 andis distributed by Eli Lilly and Company, Indianapolis, Ind.

S-Triazine compounds or 2,6-diamino-4-substituted-s-triazine-1-oxidesare described in U.S. Pat. No. 3,270,014 assigned to The Upjohn Company,Kalamazoo, Mich.

Thiane-1-oxide compounds are described in U.S. Pat. No. 4,568,682assigned to Rhone-Poulenc Sante, Courbevoie, France. Other derivativesinclude those disclosed in patent applications EP 0,321,274 A, EP0,321,273 A, and EP 0,326,297 A.

Other potassium channel openers include pyranopyridine derivativesdescribed in patent applications GB 2,204,868 A and benzopyranderivatives described in patent publications GB 2,204,868 A, EP0,314,446 A2, EP 0,339,562 A, EP 0,340,718 A, EP 0,337,179, AU A18556/88, JA 1,294,677 A, EP 0,359,537 A, and U.S. Pat. No. 4,900,752.

The phospholipids used herein may be obtained from commercial sources.The phospholipids may also be isolated from natural sources (forexample, egg yolk, soybean or other oily seed including safflower,sunflower and olive, and brain tissue) or may be produced synthetically.In either case, known techniques can be used for purification of thephospholipids (see, for example, J. of American Oil Chemists Soc.,42:53-56 (1965)).

The novel processes for preparing the novel compounds of the presentinvention are illustrated as follows, wherein R¹, R², R³, R⁵, Q, W and nare as defined above unless otherwise indicated. It will be readilyapparent to one of ordinary skill in the an reviewing the syntheticroute depicted below that other compounds within Formula I can besynthesized by substitution of appropriate reactants and agents in thesynthesis shown below. ##STR17## Reaction Scheme A

As shown in Reaction Scheme A, a solution of a 4"-hydroxy-3"-methoxymacrolide in an inert organic solvent such as methylene chloride,benzene, toluene, chloroform, or the like or mixtures thereof is treatedwith a triarylbismuth diacetate reagent (wherein R¹ is aryl) (preparedimmediately prior to use by the addition of acetic acid to a suspensionof a triarylbismuth carbonate in an inert organic solvent such asmethylene chloride, chloroform or the like or mixtures thereof) in thepresence of a catalytic amount of copper(II) acetate at a temperature of20°-50° C., preferably room temperature, for a period of one hour toseven days, preferably one day, to give the 4"-O-aryl-3"-methoxymacrolide. Alternatively, the triarylbismuth(V) reagent can be preparedby treatment of a triarylbismuthine with a suitable oxidant such asperacetic acid, iodobenzene diacetate, bis(trifluoroacetoxy)iodobenzeneand the like in an inert solvent such as methylene chloride, chloroform,benzene, toluene and the like. The triarylbismuth(V) reagent can be usedwithout purification or can be purified by silica gel chromatography.Triarylbismuthines may be prepared by the reaction of an appropriatearyl Grignard reagent with bismuth trichloride in an inert organicsolvent such as tetrahydrofuran, diethyl ether, or 1,4-dioxane, ormixtures thereof, at or near room temperature for a period of 1 to 48hours. General procedures for the preparation and use of triaryl bismuthreagents may be found in Barton, D. H. E., et al., J. Chem. Soc. Chem.Commun., 1986, 65 and references cited therein.

Reaction Scheme B

Similarly, as shown in Reaction Scheme B, a solution of the3",4"-dihydroxy macrolide is treated with a triarylbismuth diacetatereagent as described in Reaction Scheme A, to give a mixture of the3"-hydroxy-4"-O-aryl macrolide, the 3"-O-aryl-4"-hydroxy macrolide, andthe 3",4"-di-O-aryl macrolide. At this stage, a solution of3"-hydroxy-4"-O-aryl macrolide, or 3"-O-aryl-4"-hydroxy macrolide can betreated with a different triarylbismuth diacetate reagent (preparedimmediately prior to use by procedures analogous to those disclosedabove), to give 3"-O-aryl-4"-O-aryl macrolides.

Reaction Scheme C

As shown in Reaction Scheme C the 14-hydroxy group of a macrolide(wherein R¹, R², R⁵, W and n are as defined above) may be eliminated bytreatment with p-toluenesulfonic acid, benzenesulfonic acid,methanesulfonic acid, p-nitrobenzenesulfonic acid,p-bromobenzenesulfonic acid, p-chlorobenzenesulfonic acid, orp-methoxybenzene-sulfonic acid, or mixtures thereof, in an inert organicsolvent such as benzene, or toluene or the like at a temperature of 40°C. to solvent reflux temperature, preferably 60° C., for about 0.5 to 6hours, or a sufficient period of time to eliminate the 14-hydroxy group.Neutralization with an aqueous solution of a weak base such as aqueoussaturated sodium bicarbonate gives the 14,15-dehydro macrolide. The14-hydroxy group may also be eliminated by activation followed by basicelimination, as described in U.S. Pat. No. 4,894,366.

Reaction Scheme D

As shown in Reaction Scheme D the macrolide (wherein R^(1a) and/orR^(2a) is alkenyl, substituted alkenyl, alkynyl or substituted alkynyland wherein R^(3a) is hydroxy or C₁₋₆ alkoxy, R^(4a) is hydrogen, orR^(3a) and R^(4a) taken together form a double bond) is reduced under anatmosphere of hydrogen in the presence of a noble metal catalyst, suchas rhodium on carbon catalyst or rhodium on alumina catalyst, at apressure of atmospheric pressure to 40 psig, at or near room temperaturein an organic solvent such as ethyl acetate or ethanol for about 1 to 24hours, or until the requisite amount of hydrogen is absorbed to reducethe olefin and give the reduced macrolide.

By changing the sequence of synthetic steps, all possible variations ofsubstitution can be achieved. For example, the C-14 hydroxy group may beeliminated and the resultant double bond reduced prior to theintroduction of alkenyl or alkynyl substituents at C-3" and/or C-4".

Reaction Scheme E

As shown in Reaction Scheme E, a solution of the 4"-hydroxy 3"-methoxymacrolide in an inert organic solvent such as methylene chloride,chloroform, pentane, hexane, cyclohexane, heptane or the like ormixtures thereof is treated with an alkyl, alkenyl or alkynyltrichloroacetimidate reagent (prepared by the reaction of an appropriatesodium alkoxide with trichloroacetonitrile, such as described by Wessel,H. P., Iversen, T., Bundle, D. R., J. Chem. Soc., Perkin Trans. I, 1985,2247) in the presence of a mild acid catalyst such astrifluoromethanesulfonic acid, p-toluenesulfonic acid, methanesulfonicacid, benzenesulfonic acid, p-nitrobenzenesulfonic acid,p-bromobenzenesulfonic acid, p-chlorobenzenesulfonic acid, orp-methoxybenzenesulfonic acid, or mixtures thereof at a temperature of20°-50° C., preferably room temperature, for a period of one hour toseven days, preferably one day, to give the 4"-O-alkyl, -alkenyl or-alkynyl 3"-methoxy macrolide.

Reaction Scheme F

Similarly, as shown in Reaction Scheme F, (wherein R=R¹ =R²) a solutionof the 3",4"-dihydroxy macrolide in an inert organic solvent such asmethylene chloride, chloroform, pentane, hexane, cyclohexane, heptane orthe like or mixtures thereof is treated with an alkyl, alkenyl, oralkynyl trichloroacetimidate (prepared by the reaction of an appropriatesodium alkoxide with trichloroacetonitrile, such as described by Wessel,H. P., Iversen, T., Bundle, D. R., J. Chem. Soc., Perkin Trans. I, 1985,2247) in the presence of a mild acid catalyst such astrifluoromethanesulfonic acid, p-toluenesulfonic acid, methanesulfonicacid, benzenesulfonic acid, p-nitrobenzenesulfonic acid,p-bromobenzenesulfonic acid, p-chlorobenzenesulfonic acid, orp-methoxybenzene-sulfonic acid, or mixtures thereof of at a temperatureof 20°-50° C., preferably 40° C., for a period of one hour to sevendays, preferably 6 hours, to give a mixture of the 3"-O-alkyl, -alkenylor -alkynyl 4"-hydroxy macrolide, the 3"-hydroxy 4"-O-alkyl, -alkenyl or-alkynyl macrolide and the 3",4"-di-O-alkyl,-alkenyl or -alkynylmacrolide.

Reaction Scheme G

The procedures described in Reaction Schemes C and D may optionally beconducted following the procedures of Reaction Scheme E or F.Alternatively, the procedures described in Reaction Scheme G may beperformed. In Reaction Scheme G the macrolide (wherein R^(1a) and/orR^(2a) is alkenyl, substituted alkenyl, alkynyl or substituted alkynyland wherein R^(3a) is hydroxy or C₁₋₆ alkoxy, R^(4a) is hydrogen, orR^(3a) and R^(4a) taken together form a double bond) is reduced withtri-n-butyltin hydride in the presence oftetrakis-(triphenylphosphine)palladium(O) catalyst and acetic acid in anorganic solvent such as toluene or tetrahydrofuran at or near roomtemperature for about 2 to 10 hours to give the reduced macrolide.

The procedures described in Reaction Scheme F may be conducted on themono-substituted products of Reaction Scheme B (and visa versa) toobtain the mixed disubstituted compounds. In fact, within ReactionSchemes B and F, treatment of the mono-substituted product with adifferent reagent will afford the mixed disubstituted compounds.

Reaction Scheme H

Protection of the C-3", C-4" and/or the C-14 hydroxy group may beaccomplished by methods known in the prior art for compounds of FormulaII such as by treatment with: 2,6-lutidine and triisopropylsilyltrifluoromethanesulfonate in a solution of methylene chloride;2,6-lutidine and t-butyldimethylsilyl trifluoromethanesulfonate in asolution of methylene chloride; pyridine and acetic anhydride in asolution of methylene chloride; pyridine and benzoyl chloride in asolution of methylene chloride; pyridine and p-nitrobenzoyl chloride ina solution of methylene chloride; imidazole and t-butyldiphenylsilylchloride in a solution of methylene chloride; and the like. For example,as shown in Reaction Scheme H, the C-4",14-dihydroxy C-3"-methoxymacrolide (or the C-3",4",14-trihydroxy macrolide) may be protected atC-14 as the t-butyldimethylsilyl ether by treatment witht-butyldimethylsilyl trifluoromethanesulfonate in methylene chloride togive the C-4",3"-di-O-TBDMS macrolide (or the C-3",4",14-tri-O-TBDMSmacrolide). Treatment with toluenesulfonic acid in methanol results inselective removal of the C-4" silyl ether (and C-3" silyl ether, ifpresent) to give the C-14-O-TBDMS macrolide.

Reaction Scheme I

As shown in Reaction Scheme I, the 4"-hydroxy-3"-R² O-macrolide oralternatively the 3"-hydroxy-4"-R¹ O -macrolide (not depicted) (whereinR³ is protected hydroxy or hydrogen) may be reacted with an alkenyltrichloroacetimidate (wherein R¹ is C₃₋₁₀ alkenyl) under conditionsdescribed in Reaction Scheme F to give the C-4"-O-alkenyl macrolide.Treatment with a stochiometric amount of osmium tetraoxide in an inertorganic solvent, such as diethyl ether or tetrahydrofuran, in thepresence of an amine base, such as pyridine or 4-methylmorpholineN-oxide, at or near room temperature gives the corresponding glycol(wherein A is C₁₋₈ alkyl). Treatment of the glycol with sodiummetaperiodate in a solution of tetrahydrofuran/water gives the aldehyde.Alternatively, the alkenyl macrolide may be treated with sodiummetaperiodate in the presence of a catalytic amount of osmium tetraoxidein an organic solvent to give the aldehyde directly. The aldehyde can befurther oxidized to the carboxylic acid by treatment with sodiumchlorite in buffered, aqueous ten-butanol.

Reaction Scheme J

A variety of compounds may be prepared from the corresponding aldehydeas illustrated in Reaction Scheme J. The aldehyde may be reacted with aprimary or secondary amine (wherein R⁶ and R⁷ are as defined above) inan organic solvent such as tetrahydrofuran to give an imine which isreduced in situ with a hydride reducing agent, such as potassiumtriphenyl borohydride or sodium cyanoborohydride, to give the macrolidebearing an amino alkoxy functionality at C-4". The aldehyde may also bereduced to the corresponding alcohol by treatment with a hydridereducing agent, such as potassium triphenyl borohydride or sodiumcyanoborohydride in an organic solvent such as tetrahydrofuran. Thealcohol may be further modified by utilizing the methods of ReactionScheme B (wherein R¹ _(a) is unsubstituted or substituted phenyl,naphthyl or biphenyl) or Reaction Scheme F (wherein R¹ _(b) isunsubstituted or substituted alkyl, alkenyl or alkynyl). The proceduresdescribed in Reaction Scheme J are readily applicable to the preparationof compounds bearing analogous functionality at C-3".

Reaction Scheme K

Amide derivatives may be prepared from the carboxylic acid asillustrated in Reaction Scheme K. The carboxylic acid may be coupledwith a primary or secondary amine, HNR⁶ R⁷ (wherein R⁶ and/or R⁷ are asdefined) by any of the peptide coupling methods commonly used in theart, such as with BOP reagent, DCC/HOBT, or EDC/HOBT.

Reaction Scheme L

Hydroxy and keto derivatives may be prepared from the correspondingaldehyde as illustrated in Reaction Scheme L. The aldehyde is reactedwith a nucleophilic organometallic reagent such as a Grignard reagent,an organolithium reagent, or an organocerium reagent in an organicsolvent such as methylene chloride or tetrahydrofuran to give thesubstituted hydroxy compound. Removal of hydroxy protecting groups atother positions of the macrolide (if necessary) gives the macrolidebeating a substituted hydroxy alkoxy functionality at C-4". The alcoholmay also be oxidized to the corresponding ketone by well known methods,such as with 4-methylmorpholine-N-oxide in the presence oftetrapropylammonium perruthenate catalyst under dehydrative conditions.Removal of hydroxy protecting groups (if necessary) gives the macrolidebeating a substituted keto alkoxy functionality at C-4". The proceduresdescribed in Reaction Scheme L are readily applicable to the preparationof compounds beating analogous functionality at C-3".

Reaction Scheme M

Hydroxy macrolides (wherein R¹, R², and/or R³ bear a hydroxy group) maybe further derivatized by alkylation, acylation or phosphorylation togive ether, ester or phosphate derivatives (wherein R¹, R² and/or R³bear an --OR¹¹ as defined above) by procedures well known to thepractitioner of the art.

Reaction Scheme N

As illustrated in Scheme N, the hydroxy macrolide may be derivatized bytreatment with a substituted alpha-diazoketone in an inert organicsolvent such as methylene chloride in the presence of a catalyst such asrhodium acetate to provide the corresponding ether adduct. The ketonefunctionality of the appended ether may be selectively reduced in aninert organic solvent such as diethyl ether or tetrahydrofuran at -78°C. by treatment with a reducing agent, such as L-Selectride, potassiumtriphenlyborohydride, diisobutyl aluminum hydride or lithiumtriethylborohydride.

Reaction Scheme O

Alternatively, as shown in Scheme O, treatment of the hydroxy macrolidewith a substituted 2-diazoacetophenone in an inert organic solvent suchas methylene chloride with a Lewis acid catalyst such as borontrifluoride etherate provides the corresponding ether adduct.

The object compounds of Formula I obtained according to the reactions asexplained above can be isolated and purified in a conventional manner,for example, extraction, precipitation, fractional crystallization,recrystallization, chromatography, and the like.

It is to be noted that in the aforementioned reactions and thepost-treatment of the reaction mixture therein, the stereoisomer(s) ofstarting and object compounds due to asymmetric carbon atom(s) or doublebond(s) of the object compounds of Formula I may occasionally betransformed into the other stereoisomer(s), and such cases are alsoincluded within the scope of the present invention.

In the present invention, compounds with asymmetric centers may occur asracemates, as diastereomeric mixtures and as individual diastereomers,with all isomeric forms of the compounds being included in the presentinvention. These may be prepared by methods such as those disclosed inpublications which describe synthetic routes to fragments of themacrolide FR-900506 and the total synthesis of the macrolide FR-900506itself (See for example, J. Am. Chem. Soc., 1989, 111, 1157; J. Am.Chem. Soc., 1990, 112, 2998; J. Org. Chem., 1990, 55, 2786; J. Am. Chem.Soc., 1990, 112, 5583. Tetrahedron Lett., 1988, 29, 277; TetrahedronLett., 1988, 29,281; Tetrahedron Lett., 1988, 29, 3895; J. Org. Chem.,1988, 53, 4643; Tetrahedron Lett., 1988, 29, 4245; Tetrahedron Lett.,1988, 29, 4481; J. Org. Chem., 1989, 54, 9; J. Org. Chem., 1989, 54, 11;J. Org. Chem., 1989, 54, 12; J. Org. Chem., 1989, 54, 15; J. Org. Chem.,1989, 54, 17; Tetrahedron Lett., 1989, 30, 919; Tetrahedron Lett., 1989,30, 1037; J. Org. Chem., 1989, 54, 2785; J. Org. Chem., 1989, 54, 4267;Tetrahedron Lett., 1989, 30, 5235; Tetrahedron Lett., 1989, 30, 6611;Tetrahedron Lett., 1989, 30, 6963; Synlett 1990, 38; J. Org. Chem.,1990, 55, 2284; J. Org. Chem., 1990, 55, 2771; J. Org. Chem., 1990, 55,2776; Tetrahedron Lett., 1990, 31, 1439; Tetrahedron Lett., 1990, 31,1443; Tetrahedron Lett., 1990, 31, 3007; Tetrahedron Lett., 1990, 31,3283, 3287).

The compounds of the present invention are capable of forming salts withvarious inorganic and organic acids and bases and such salts are alsowithin the scope of this invention. Examples of such acid addition salts(which are negative counterions defined herein as M⁻) include acetate,adipate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate,camphorate, camphorsulfonate, ethanesulfonate, fumarate, hemisulfate,heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide,methanesulfonate, lactate, maleate, methanesulfonate,2-naphthalenesulfonate, oxalate, pamoate, persulfate, picrate, pivalate,propionate, succinate, tartrate, tosylate, and undecanoate. Base salts(which are positive counterions defined herein as M⁺) include ammoniumsalts, alkali metal salts such as sodium, lithium and potassium salts,alkaline earth metal salts such as calcium and magnesium salts, saltswith organic bases such as dicyclohexylamine salts,N-methyl-D-glucamine, and salts with amino acids such as arginine,lysine and so forth. Also, the basic nitrogen-containing groups may bequaternized with such agents as: lower alkyl halides, such as methyl,ethyl, propyl, and butyl chloride, bromides and iodides; dialkylsulfates like dimethyl, diethyl, dibutyl; diamyl sulfates; long chainhalides such as decyl, lauryl, myristyl and stearyl chlorides, bromidesand iodides; aralkyl halides like benzyl bromide and others. Thenon-toxic physiologically acceptable salts are preferred, although othersalts are also useful, such as in isolating or purifying the product.

The salts may be formed by conventional means, such as by reacting thefree base form of the product with one or more equivalents of theappropriate acid in a solvent or medium in which the salt is insoluble,or in a solvent such as water which is removed in vacuo or by freezedrying or by exchanging the anions of an existing salt for another anionon a suitable ion exchange resin.

C. Utility of the compounds within the scope of the invention

The compounds of Formula I may be employed as immunosuppressants orantimicrobial compounds by methods and in dosages known in the prior anfor compounds of Formula II. These compounds possess pharmacologicalactivity such as immunosuppressive activity, antimicrobial activity, andthe like, and therefore are useful for the treatment and prevention ofthe resistance to transplantation or transplantation rejection of organsor tissues (such as heart, kidney, liver, lung, bone marrow, cornea,pancreas, intestinum tenue, limb, muscle, nervus, medulla ossium,duodenum, small-bowel, medulla ossium, skin, pancreatic islet-cell, etc.including xeno transplantation), graft-versus-host diseases by medullaossium transplantation, autoimmune diseases such as rheumatoidarthritis, systemic lupus erythematosis, nephrotic syndrome lupus,Hashimoto's thyroiditis, multiple sclerosis, myasthenia gravis, type Idiabetes mellitus, type II adult onset diabetes, uveitis, nephroticsyndrome, steroid-dependent and steroid-resistant nephrosis,Palmo-planter pustulosis, allergic encephalomyelitis,glomerulonephritis, etc., and infectious diseases caused by pathogenicmicroorganisms.

The compounds of Formula I are also useful for treating inflammatory,proliferative and hyperproliferative skin diseases and cutaneousmanifestations of immunologically-mediated illnesses such as: psoriasis,psoriatic arthritis, atopical dermatitis, contact dermatitis and furthereczematous dermatitises, seborrhoeic dermatitis, Lichen planus,Pemphigus, bullous Pemphigoid, Epidermolysis bullosa, urticaria,angioedemas, vasculitides, erythemas, cutaneous eosinophilias, acneAlopecia areata, eosinophilic fasciitis, and atherosclerosis. Moreparticularly, the compounds of Formula I are useful in hairrevitalizing, such as in the treatment of male or female patternalopecia or alopecia senilis, by providing epilation prevention, hairgermination, and/or a promotion of hair generation and hair growth.

The compounds of Formula I are further useful in the treatment ofrespiratory diseases, for example sarcoidosis, fibroid lung, idiopathicinterstitial pneumonia, and reversible obstructive airways disease,including conditions such as asthma, including bronchial asthma,allergic asthma, intrinsic asthma, extrinsic asthma and dust asthma,particularly chronic or inveterate asthma (for example late asthma andairway hyperresponsiveness), bronchitis and the like. The compounds ofFormula I may also be useful for treating hepatic injury associated withischemia.

The compounds of the invention are also indicated in certain eyediseases such as keratoconjunctivitis, vernal conjunctivitis, uveitisassociated with Behcet's disease, keratitis, herpetic keratitis, conicalcornea, dystorphia epithelialis corneae, corneal leukoma, ocularpemphigus, Mooren's ulcer, Scleritis, Graves' ophthalmopathy, severeintraocular inflammation, and the like.

The compounds of Formula I are also useful for treating multidrugresistance of tumor cells, (i.e. enhancing the activity and/orsensitivity of chemotherapeutic agents), preventing or treatingintimation of mucosa or blood vessels (such as leukotriene B₄ -mediateddiseases, gastric ulcers, vascular damage caused by ischemic diseasesand thrombosis, ischemic bowel disease, inflammatory bowel disease(e.g., Crohn's disease and ulcerative colitis) necrotizingenterocolitis), or intestinal lesions associated with thermal bums,cytomegalovirus infection, particularly HCMV infection.

Further, the compounds of Formula I are also useful for treating orpreventing renal diseases including interstitial nephritis,Goodpasture's syndrome, hemolytic-uremic syndrome and diabeticnephropathy; nervous diseases selected from multiple myositis,Guillain-Barre syndrome, Meniere's disease and radiculopathy; endocrinediseases including hyperthyroidism and Basedow's disease; hematicdiseases including pure red cell aplasia, aplastic anemia, hypoplasticanemia, idiopathic thrombocytopenic purpura, autoimmune hemolyticanemia, agranulocytosis and anerythroplasia; bone diseases includingosteoporosis; respiratory diseases including sarcoidosis, fibroid lungand idiopathic interstitial pneumonia; skin diseases includingdermatomyositis, leukoderma vulgaris, ichthyosis vulgaris, photoallergicsensitivity and cutaneous T cell lymphoma; circulatory diseasesincluding arteriosclerosis, aortitis syndrome, polyarteritis nodosa andmyocardosis; collagen including scleroderma, Wegener's granuloma andSjogren's syndrome; adiposis; eosinophilic fasciitis; periodontaldisease; nephrotic syndrome; hemolytic-uremic syndrome; and musculardystrophy.

Further, the compounds of the invention are indicated in the treatmentof diseases including intestinal inflammations/allergies such as Coeliacdisease, proctitis, eosinophilic gastroenteritis, mastocytosis, Crohn'sdisease and ulcerative colitis; and food related allergic diseases whichhave symptomatic manifestation remote from the gastrointestinal tract,for example migraine, rhinitis and eczema.

The compounds of the invention also have liver regenerating activityand/or activity in stimulating hypertrophy and hyperplasia ofhepatocytes. Therefore, they are useful for the treatment and preventionof hepatic diseases such as immunogenic diseases (e.g. chronicautoimmune liver diseases including autoimmune hepatitis, primarybiliary cirrhosis and sclerosing cholangitis), partial liver resection,acute liver necrosis (e.g. necrosis caused by toxins, viral hepatitis,shock or anoxia), B-virus hepatitis, non-A/non-B hepatitis andcirrhosis.

The compounds of the invention are also indicated for use asantimicrobial agents, and thus may be used in the treatment of diseasescaused by pathogenic microorganisms and the like.

The compounds of Formula I may also be useful in the prevention ortreatment of immunodepression (such as AIDS, HIV infection, cancer,senile dementia, trauma (including wound healing, surgery and shock),chronic bacterial infection and certain central nervous systemdisorders), overdosages or toxicity of such immunosuppressive compounds,and as an adjunct to the administration of an antigen in vaccination.

The pharmaceutical compositions of this invention can be used in theform of a pharmaceutical preparation, for example, in solid, semisolidor liquid form, which contains one or more of the compounds of thepresent invention, as an active ingredient, in admixture with an organicor inorganic carrier or excipient suitable for external, enteral orparenteral applications. The active ingredient may be compounded, forexample, with the usual non-toxic, pharmaceutically acceptable carriersfor tablets, pellets, capsules, suppositories, solutions, emulsions,suspensions, and any other form suitable for use. The carriers which canbe used are water, glucose, lactose, gum acacia, gelatin, mannitol,starch paste, magnesium trisilicate, talc, corn starch, keratin,colloidal silica, potato starch, urea and other carriers suitable foruse in manufacturing preparations, in solid, semisolid, or liquid form,and in addition auxiliary, stabilizing, thickening and coloring agentsand perfumes may be used. For example, the compounds of Formula I may beutilized with hydroxypropyl methylcellulose essentially as described inU.S. Pat. No. 4,916,138, issued Apr. 10, 1990, or with a surfactantessentially as described in EPO Publication 0,428,169. Oral dosage formsmay be prepared essentially as described by T. Hondo, et al.,Transplantation Proceedings, 1987, XIX, Supp. 6, 17-22. Dosage forms forexternal application may be prepared essentially as described in EPOPublication 0,423,714. The active object compound is included in thepharmaceutical composition in an amount sufficient to produce thedesired effect upon the process or condition of diseases.

For the treatment of these conditions and diseases caused byimmmunoirregularity a compound of Formula I may be administered orally,topically, parenterally, by inhalation spray or rectally in dosage unitformulations containing conventional non-toxic pharmaceuticallyacceptable carriers, adjuvants and vehicles. The term parenteral as usedherein includes subcutaneous injections, intravenous, intramuscular,intrasternal injection or infusion techniques.

For the treatment of reversible obstructive airways disease, it ispreferable that the compound of Formula I be administered by inhalationto the lung, especially in the form of a powder.

For modifying the activity and/or toxicity of FK-506-typeimmunosuppressants, a compound of Formula I may be administered priorto, in conjuction with or subsequent to the administration of anFK-506-type of a compound.

The compounds of Formula I may optionally be employed in co-therapy withanti-proliferative agents. Particularly preferred is co-therapy with anantiproliferative agent selected from the group consisting ofazathioprine (AZA), brequinar sodium, deoxyspergualin (DSG), mizaribine,mycophenolic acid morpholino ester (RS-61443), cyclosporin andrapamycin.

The compounds of Formula I may also be employed in conjunction with (orin a pharmaceutical composition additionally comprising):

(1) a 5α-reductase inhibitor,

(2) a cyclosporin,

(3) a potassium channel opener (such as minoxidil), or

(4) a phospholipid.

Such co-therapy is particularly useful in hair revitalizing, such as inthe treatment of male pattern alopecia, female pattern alopecia,alopecia senilis or Alopecia areata, by providing epilation prevention,hair germination, and/or a promotion of hair generation and hair growth.

Such co-therapy is further useful in treating the hyperandrogenicconditions of androgenic alopecia, acne vulgaris, seborrhea, and femalehirsutism.

For co-therapy of these conditions and diseases a compound of Formula Imay be administered in combination with prior to, concurrent to, orsubsequent to the administration of other agent(s).

For hair revitalizing the compound of Formula I may be administeredtopically or orally. Cyclosporin may be administered topically ororally. Although the 5α-reductase inhibitor or the potassium channelopener may be administered topically or orally, it is preferable that itbe administered topically to the scalp. For unitary formulation,however, the preferred mode of administration is topically. It isespecially preferred that the hair revitalizing composition of thepresent invention is administered by a percutaneous administration or byspraying onto the skin.

Dosage levels of the compounds of the present invention are of the orderfrom about 0.005 mg to about 50 mg per kilogram of body weight per day,preferably from about 0.1 mg to about 10 mg per kilogram of body weightper day, are useful in the treatment of the above-indicated conditions(from about 0.7 mg to about 3.5 mg per patient per day, assuming a 70 kgpatient). In addition, the compounds of the present invention may beadministered on an intermittent basis; i.e. at daily, semiweekly,weekly, semi-monthly or monthly intervals.

The amount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. For example, aformulation intended for the oral administration of humans may containfrom 0.5 mg to 5 gm of active agent compounded with an appropriate andconvenient amount of carrier material which may vary from about 5 toabout 95 percent of the total composition. Dosage unit forms willgenerally comprise from about 0.01 mg to about 500 mg, and preferablyabout 0.5 mg to about 100 mg of active ingredient. For externaladministration the compound of Formula I may be formulated within therange of, for example, 0.0001% to 60% by weight, preferably from 0.001to 10% by weight, and most preferably from about 0.005 to 0.8% byweight.

It will be understood, however, that the specific dose level for anyparticular patient will depend on a variety of factors including theactivity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration, rate of excretion, drag combination and the severity ofthe particular disease undergoing therapy.

The following examples are given for the purpose of illustrating thepresent invention and shall not be construed as being limitations on thescope or spirit of the instant invention.

EXAMPLE 1

17-Ethyl-1,14-dihydroxy-12-2'-(4"-phenyloxy-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

To a stirred solution of 17-ethyl-1,14-dihydroxy-12-2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (100 mg, 0.126 mmol, 1eq) and Cu(OAc)₂ (2.8 mg, 0.014 mmol, 0.11 eq) in CH₂ Cl₂ (1 ml) in a 16mL screw-cap vial equipped with a magnetic stir-bar was added triphenylbismuth diacetate prepared immediately prior to use by addition ofacetic acid (0.030 mL, 0.504 mmol, 4 eq) to a suspension of triphenylbismuth carbonate (127 mg, 0.253 mmol, 2 eq) in CH₂ Cl₂ (1 ml)!. Thereaction vessel was capped and the mixture stirred for five days. Thereaction mixture was diluted with several milliliters of saturatedaqueous NaHCO₃ and extracted 4 times with CH₂ Cl₂. The organic extractswere combined, dried over anhydrous Na₂ SO₄, filtered and concentratedin vacuo. The product was isolated by preparative TLC on silica gel(eluted with 3:4 EtOAc/hexanes to afford 46 mg of17-ethyl-1,14-dihydroxy 12-2'-(4"-phenyloxy-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone. (¹ H NMR, ¹³ C NMR andmass spectral analysis were consistent with the desired structure.)

EXAMPLE 2

A. 17-Ethyl-1,14-dihydroxy-12-2'-(3"-phenyloxy-4"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9!octacos-18-ene-2,3,10,16-tetraone and

B. 17-Ethyl-1,14-dihydroxy-12-2'-(4"-phenyloxy-3"-hydroxy-cyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,-27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

To a stirred solution of 17-ethyl-1,14-dihydroxy-12-2'-(3",4"-dihydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (500 mg, 0.644 mmol, 1eq) and Cu(OAc)₂ (12 mg, 0.064 mmol, 0.1 eq) in CH₂ Cl₂ (10 ml) in a 25ml recovery flask equipped with a magnetic stir-bar was added triphenylbismuth diacetate prepared immediately prior to use by addition ofacetic acid (0.220 ml, 3.860 mmol, 6 eq) to a suspension of triphenylbismuth carbonate (483 mg, 0.965 mmol, 1.5 eq) in CH₂ Cl₂ (10 ml)!. Thereaction flask was capped and the mixture stirred at room temperaturefor 6 hours. The flask was then fitted with a condenser and the mixturewas warmed to 40° C. After 40 hours the reaction mixture was cooled,diluted with saturated aqueous NaHCO₃ and extracted 4 times with CH₂Cl₂. The organic extracts were combined, dried over anhydrous Na₂ SO₄,filtered and concentrated in vacuo. The products were separated andpurified by flash column chromatography on silica gel eluted with 4:1hexanes/acetone followed by preparative TLC on silica gel (eluted with2:1 hexanes/acetone! to yield 94 mg of 17-ethyl-1,14-dihydroxy-12-2'-(4"-phenyloxy-3"-hydroxycyclohexyl)-1'-methyl-vinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone and 110 mg of17-ethyl-1,14-dihydroxy-12-2'-(3"-phenyloxy-4"-hydroxycyclo-hexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21, 27-tetramethyl-11,28-dioxa-4-azatricyclo 22.3.1.0⁴,9!octacos-18-ene-2,3,10,16-tetraone. (¹ H NMR, ¹³ C NMR and mass spectralanalysis were consistent with the desired structure).

EXAMPLE 3

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(4'"-fluorophenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

To a stirred mixture of 17-ethyl-1,14-dihydroxy-12-2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (100 mg, 0.126 mmol, 1eq) and Cu(OAc)₂ (3 mg, 0.0165 mmol, 0.13 eq) in CH₂ Cl₂ (1 ml) in a 4mL screw-cap vial equipped with a magnetic stir-bar was addedtri(4-fluorophenyl)-bismuth diacetate prepared immediately prior to useby addition of acetic acid (0.030 mL, 0.504 mmol, 4 eq) to a suspensionof tri(4-fluorophenyl)bismuth carbonate (100 mg, 0.181 mmol, 1.4 eq) inCH₂ Cl₂ (1 mL)!. The reaction vessel was capped and the mixture stirredfor two days. The reaction mixture was diluted with several millilitersof saturated aqueous NaHCO₃ and extracted 2 times with CH₂ Cl₂. Theorganic extracts were combined, dried over anhydrous Na₂ SO₄, filteredand concentrated in vacuo. The product was isolated by preparative TLCon silica gel (eluted with 3:1 hexanes/EtOAc) to afford 39 mg of17-ethyl-1,14-dihydroxy-12-2'-(4"-(4'"-fluoro-phenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone. (¹ H NMR, ¹³ C NMR andmass spectral analysis were consistent with the desired structure).

EXAMPLE 4

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(4'"-chlorophenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

To a stirred mixture of 17-ethyl-1,14-dihydroxy-12-2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (150 mg, 0.189 mmol, 1eq) and Cu(OAc)₂ (6.1 mg, 0.033 mmol, 0.17 eq) in CH₂ Cl₂ (2.5 ml) in around bottom flask equipped with a magnetic stir-bar was addedtri(4-chlorophenyl)-bismuth diacetate prepared immediately prior to useby addition of acetic acid (0.075 ml, 1.3 mmol, 6.9 eq) to a suspensionof tri(4-chlorophenyl)-bismuth carbonate (200 mg, 0.331 mmol, 1.75 eq)in CH₂ Cl₂ (2.5 ml)!. The reaction flask was then fitted with a refluxcondenser and the mixture warmed to 40° C. After 20 hours the reactionmixture was cooled, diluted with saturated aqueous NaHCO₃ (10 mL) andextracted 4 times with CH₂ Cl₂. The organic extracts were dried overanhydrous Na₂ SO₄, filtered and concentrated in vacuo. The product wasseparated and purified two times by preparative TLC on silica gel(eluted with 2:1 hexanes/acetone) to give 40 mg17-ethyl-1,14-dihydroxy-12-2'-(4"-(4'"-chlorophenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone. (¹ H NMR, ¹³ C NMR, andmass spectral analysis were consistent with the desired structure).

EXAMPLE 5

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(4'"-methylphenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

To a stirred mixture of 17-ethyl-1,14-dihydroxy-12-2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (100 mg, 0.126 mmol, 1eq) and Cu(OAc)₂ (3 mg, 0.0165 mmol, 0.13 eq) in CH₂ Cl₂ (1 ml) in a 4mL screw cap vial equipped with a magnetic stir-bar was addedtri(4-tolyl)bismuth diacetate prepared immediately prior to use byaddition of acetic acid (0.030 ml, 0.525 mmol, 4.2 eq) to a suspensionof tri(4-tolyl)bismuth carbonate (130 mg, 0.234 mmol, 1.86 eq) in CH₂Cl₂ (1 ml)!. The reaction vessel was capped and the mixture stirred for20 hours at which time TLC analysis showed the reaction to beincomplete. The mixture was treated with additional tri(4-tolyl) bismuthdiacetate (0.234 mmol) and stirred for 24 hours then poured intosaturated aqueous NaHCO₃ and extracted 2 times with CH₂ Cl₂. The organicextracts were combined, dried over anhydrous Na₂ SO₄, filtered andconcentrated in vacuo. The product was isolated by preparative TLC onsilica gel (eluted with 2:1 hexanes/EtOAc) to give 47 mg17-ethyl-1,14-dihydroxy-12-2'-(4"-(4'"-methylphenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone. (¹ H NMR, ¹³ C NMR, andmass spectral analysis were consistent with the desired structure.)

EXAMPLE 6

A. 17-Ethyl-1,14-dihydroxy-12-2'-(3"-(4'"-methylphenyloxy)-4"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !-octacos-18-ene-2,3,10,16-tetraone and

B. 17-Ethyl-1,14-dihydroxy-12-2'-(4"-(4'"-methylphenyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !-octacos-18-ene -2,3,10,16-tetraone

To a stirred mixture of 17-ethyl-1,14-dihydroxy-12-2'-(3",4"-dihydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (200 mg, 0.257 mmol, 1eq) and Cu(OAc)₂ (10 mg, 0.055 mmol, 0.2 eq) in CH₂ Cl₂ (2 ml) in around bottom flask equipped with a magnetic stir-bar was addedtri(4-tolyl)bismuth diacetate prepared immediately prior to use byaddition of acetic acid (0.075 ml, 1.31 mmol, 5.1 eq) to a suspension oftri(4-tolyl) bismuth carbonate (300 mg, 0.553 mmol, 2.1 eq) in CH₂ Cl₂(2 ml)!. The reaction flask was fitted with a reflux condenser and themixture warmed to 40° C. for 5 hours then stirred without heating. After18 hours the reaction mixture was diluted with saturated aqueous NaHCO₃and extracted 2 times with CH₂ Cl₂. The organic extracts were combined,dried over anhydrous Na₂ SO₄, filtered and concentrated in vacuo. Theproducts were separated and purified by preparative TLC on silica gel(eluted with 2:1 hexanes/acetone) to afford 31 mg of17-ethyl-1,14-dihydroxy-12-2'-(3"-(4'"-methylphenyloxy)-4"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone and 42 mg of17-ethyl-1,14-dihydroxy-12-2'-(4"-(4'"-methylphenyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone. (¹ H NMR and ¹³ C NMRanalysis were consistent with the desired structures).

EXAMPLE 7

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(4'"-phenoxyphenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

A stirred mixture of 17-ethyl-1,14-dihydroxy-12-2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (150 mg, 0.19 mmol, 1 eq)and Cu(OAc)₂ (6.0 mg, 0.033 mmol, 0.17 eq) in CH₂ Cl₂ (2.5 ml) in around bottom flask equipped with a magnetic stir-bar and a refluxcondenser was heated to 40° C. then treated withtri(4-phenoxyphenyl)bismuth diacetate prepared immediately prior to useby addition of acetic acid (0.075 mL, 1.31 mmol, 6.9 eq) to a suspensionof tri(4-phenoxyphenyl)bismuth carbonate (225 mg, 0.29 mmol, 1.5 eq) inCH₂ Cl₂ (2.5 ml)!. After 18 hours TLC analysis showed the reaction to beincomplete and additional tri(4-phenoxyphenyl)bismuth diacetate (0.10mmol) was added. The reaction mixture was stirred with heating for 5hours then cooled, diluted with saturated aqueous NaHCO₃, and extracted2 times with CH₂ Cl₂. The extracts were combined, dried over Na₂ SO₄,filtered, and concentrated in vacuo. The product was isolated andpurified by preparative TLC on silica gel (2:1 hexanes/acetone) to give66 mg of 17-ethyl-1,14-dihydroxy-12-2'-(4"-(4'"-phenoxyphenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone. (¹ H NMR, ¹³ C NMR, andmass spectral analysis were consistent with the desired structure).

EXAMPLE 8

A. 17-Ethyl-1,14-dihydroxy-12-2'-(4"-(4'"-phenoxyphenyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !-octacos-18-ene-2,3,10,16-tetraone and

B. 17-Ethyl-1,14-dihydroxy-12-2'-(3"-(4'"-phenoxyphenyloxy)-4"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !-octacos-18-ene-2,3,10,16-tetraone

To a stirred mixture of 17-ethyl-1,14-dihydroxy-12-2'-(3",4"-dihydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (150 mg, 0.19 mmol, 1 eq)and Cu(OAc)₂ (7 mg, 0.039 mmol, 0.21 eq) in CH₂ Cl₂ (2 mL) in a roundbottom flask equipped with a magnetic stir-bar was addedtri(4-phenoxyphenyl)bismuth diacetate prepared immediately prior to useby addition of acetic acid (0.070 ml, 1.22 mmol, 6.4 eq) to a suspensionof tri(4-phenoxyphenyl)bismuth carbonate (230 mg, 0.30 mmol, 1.58 eq) inCH₂ Cl₂ (2 mL)!. The reaction flask was fitted with a reflux condenserand the mixture warmed to 40° C. After 4 hours the mixture was cooled,diluted with saturated aqueous NaHCO₃, and extracted 2 times with CH₂Cl₂. The extracts were combined, dried over Na₂ SO₄, filtered, andconcentrated in vacuo. The products were separated and purified 3× bypreparative TLC on silica gel (3:2 hexanes/acetone) to afford 35 mg of17-ethyl-1,14-dihydroxy-12-2'-(4"-(4'"-phenoxyphenyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone and 42 mg of17-ethyl-1,14-dihydroxy-12-2'-(3"-(4'"-phenoxyphenyloxy)-4"-hydroxycyclohexyl)-1'-methyl-vinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone. (¹ H NMR, ¹³ C NMR, andmass spectral analysis were consistent with the desired structures).

EXAMPLE 9

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(naphth-1-yloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

To a stirred mixture of 17-ethyl-1,14-dihydroxy-12-2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (150 mg, 0.19 mmol, 1 eq)and Cu(OAc)₂ (6 mg, 0.033 mmol, 0.17 eq) in CH₂ Cl₂ (2 ml) in a roundbottom flask equipped with a magnetic stir-bar was addedtri(1-naphthyl)bismuth diacetate prepared immediately prior to use byaddition of acetic acid (0.070 ml, 1.22 mmol, 6.4 eq) to a suspension oftri(1-naphthyl)bismuth carbonate (150 mg, 0.23 mmol, 1.2 eq)in CH₂ Cl₂(2 ml)!. The reaction flask was then fitted with a reflux condenser a2nd the mixture was warmed to 40° C. for 4 hours. After stirring anadditional 16 hours at room temperature TLC analysis showed the reactionto be incomplete. The reaction mixture was further treated withtri(1-naphthyl)bismuth diacetate (0.15 mmol) and heated to 40° C. for 4hours. The mixture was cooled, diluted with saturated aqueous NaHCO₃,and extracted 2 times with CH₂ Cl₂. The extracts were combined, driedover anhydrous Na₂ SO₄, filtered, and concentrated in vacuo. The productwas isolated and purified 2 times by preparative TLC on silica gel (3:1hexanes/acetone) to give 38 mg of 17-ethyl-1,14-dihydroxy-12-2'-(4"-(naphth-1-yloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-22.3.1.0⁴,9 !-octacos-18-ene-2,3,10,16-tetraone. (¹ H NMR analysis wasconsistent with the desired structure).

EXAMPLE 10

A. 17-Ethyl-1,14-dihydroxy-12-2'-(3"-(naphth-1-yloxy)-4"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone and

B. 17-Ethyl-1,14-dihydroxy-12-2'-(4"-(naphth-1-yl-oxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !-octacos-18-ene-2,3,10,16-tetraone

To a stirred mixture of 17-ethyl-1,14-dihydroxy-12-2'-(3",4"-dihydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (250 mg, 0.32 mmol, 1 eq)and Cu(OAc)₂ (15 mg, 0.08 mmol, 0.25 eq) in CH₂ Cl₂ (5 ml) in a roundbottom flask equipped with a magnetic stir-bar was added tri(1-naphthyl)bismuth diacetate prepared immediately prior to use by addition ofacetic acid (0.100 ml, 1.75 mmol, 5.46 eq) to a suspension oftri(1-naphthyl) bismuth carbonate (350 mg, 0.54 mmol, 1.69 eq) in CH₂Cl₂ (5 ml)!. The reaction flask was fitted with a reflux condenser andthe mixture warmed to 40° C. for 5 hours then stirred at roomtemperature. After 16 hours the mixture was diluted with saturatedaqueous NaHCO₃ and extracted 2 times with CH₂ Cl₂. The extracts werecombined, dried over anhydrous Na₂ SO₄, filtered, and concentrated invacuo. The products were separated and purified by preparative TLC onsilica gel (eluted with 3:1 hexanes/acetone) to yield 49 mg of17-ethyl-1,14-dihydroxy-12-2'-(3"-(naphth-1-yloxy)-4"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone and 39 mg of17-ethyl-1,14-dihydroxy-12-2'-(4"-(naphth-1-yloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-1,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !-octacos-18-ene-2,3,10,16-tetraone. (¹ H NMR analysis wasconsistent with the desired structure).

EXAMPLE 11

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(naphth-2-yloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

To a stirred mixture of 17-ethyl-1,14-dihydroxy-12-2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (150 mg, 0.189 mmol, 1eq) and Cu(OAc)₂ (6 mg, 0.033 mmol, 0.17 eq) in CH₂ Cl₂ (2.5 mL) in around bottom flask equipped with a magnetic stir-bar was addedtri(2-naphthyl)-bismuth diacetate prepared immediately prior to use byaddition of acetic acid (0.075 ml, 1.31 mmol, 6.9 eq) to a suspension oftri(2-naphthyl)bismuth carbonate in CH₂ Cl₂ (2.5 ml)!. The reactionflask was fitted with a reflux condenser and the mixture warmed to 40°C. After 4 hours the heating was discontinued and the mixture stirred atroom temperature for 16 hours. The mixture was then diluted withsaturated aqueous NaHCO₃ and extracted 2 times with CH₂ Cl₂. Theextracts were combined, dried over anhydrous Na₂ SO₄, filtered, andconcentrated in vacuo. The product was isolated and purified bypreparative TLC on silica gel (3:1 hexanes/acetone) to afford 32 mg of17-ethyl-1,14-dihydroxy-12-2'-(4"-(naphth-2-yloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !-octacos-18-ene-2,3,10,16-tetraone. (¹ H NMR, ¹³ C NMR, andmass spectral analysis were consistent with the desired structure).

EXAMPLE 12

A. 17-Ethyl-1,14-dihydroxy-12-2'-(4"-(naphth-2-yloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone and

B. 17-Ethyl-1,14-dihydroxy-12-2'-(3"-(naphth-2-yloxy)4"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

To a stirred mixture of 17-ethyl-1,14-dihydroxy-12-2'-(3",4"-dihydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,-10,16-tetraone (250 mg, 0.32 mmol, 1eq) and Cu(OAc)₂ (10 mg, 0.055 mmol, 0.17 eq) in CH₂ Cl₂ (5.5 ml) in around bottom flask equipped with a magnetic stir-bar was addedtri(2-naphthyl)bismuth diacetate prepared immediately prior to use byaddition of acetic acid (0.100 mL, 1.75 mmol, 5.46 eq) to a suspensionof tri(2-naphthyl)bismuth carbonate (350 mg, 0.538 mmol, 1.7 eq) in CH₂Cl₂ (5.5 ml)!. The reaction flask was fitted with a reflux condenser andthe mixture warmed to 40° C. for 4 hours then stirred at roomtemperature. After 3 days the reaction mixture was diluted withsaturated aqueous NaHCO₃ and extracted 3 times with CH₂ Cl₂. Theextracts were combined, dried over anhydrous Na₂ SO₄, filtered, andconcentrated in vacuo. The products were separated and purified bypreparative TLC on silica gel (eluted with 3:1 hexanes/acetone) to give63 mg of 17-ethyl-1,14-dihydroxy-12-2'-(3"-(napth-2-yloxy)-4"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone and 49 mg of17-ethyl-1,14-dihydroxy-12-2'-(4"-(naphth-2-yloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone.

(¹ H NMR was consistent with the desired structure).

EXAMPLE 13

17-Ethyl-1-hydroxy-12-2'-(4"-(naphth-2-yloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

To a stirred mixture of 17-ethyl-1-hydroxy-12-2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (300 mg, 0.39 mmol, 1 eq)and Cu(OAc)₂ (15 mg, 0.083 mmol, 0.21 eq) in CH₂ Cl₂ (5 ml) in a roundbottom flask equipped with a magnetic stir-bar was addedtri(2-naphthyl)bismuth diacetate prepared immediately prior to use byaddition of acetic acid to a suspension of tri(2-naphthyl)bismuthcarbonate (300 mg, 0.461 mmol, 1.2 eq) in CH₂ Cl₂ (5 ml)!. The reactionflask was fitted with a reflux condenser and the mixture warmed to 40°C. After 6 hours the mixture was allowed to cool to room temperature andstirred an additional 16 hours. The reaction mixture was diluted withsaturated aqueous NaHCO₃ and extracted 2 times with CH₂ Cl₂. Theextracts were combined, dried over anhydrous Na₂ SO₄, filtered, andconcentrated in vacuo. The product was isolated and purified bypreparative TLC (3:1 hexanes/acetone) to give 109 mg of17-ethyl-1-hydroxy-12-2'-(4"-(naphth-2-yloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone. (¹ H NMR and ¹³ C NMRanalysis were consistent with the desired structure).

EXAMPLE 14

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(6'"-methoxy-naphth-2-yloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

To a solution of tri-(6-methoxy-2-naphthyl)bismuth diacetate (52 mg,0.069 mmol, 1.1 eq) in methylene chloride (2 ml) in a 10 ml round bottomflask equipped with a stir bar was added 17-ethyl-1,14-dihydroxy-12-2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (50 mg, 0.063 mmol, 1eq). To the reaction mixture was added a catalytic amount of Cu(OAc)₂(approximately 20 mg). The reaction flask was fitted with a refluxcondenser and the mixture was warmed to 40° C. After 1 hour the mixturewas cooled, diluted with saturated aqueous NaHCO₃ and extracted 4 timeswith CH₂ Cl₂. The organic extracts were combined, dried over anhydrousNa₂ SO₄, filtered and concentrated in vacuo. The product was isolated bytwo preparative thin layer chromatographys on silica gel (firstchromatography eluted with 2:1 hexanes/acetone, isolated band at R_(f)=0.26 second chromatography eluted with 3.5% methanol/CH₂ Cl₂, isolatedband at R_(f) =0.62) to give 20 mg of 17-ethyl-1,14-dihydroxy-12-2'-(4"-(6'"-methoxy-naphth-2-yloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone.

(¹ H NMR and mass spectral analysis were consistent with the desiredstructure).

EXAMPLE 14A

General procedure for the preparation of triarylbismuthines

To a stirred suspension of magnesium (486 mg, 20 mmol) in drytetrahydrofuran (10 mL) is added slowly a solution of aryl halide (20mmol) in dry tetrahydrofuran (10 mL). If necessary, the mixture iswarmed gently to effect Grignard formation. To the stirred solution ofthe Grignard reagent is added a solution of bismuth trichloride (1.9 g,6 mmol) dissolved in dry tetrahydrofuran (20 mL). The resulting mixtureis stirred for 24 hours. The reaction mixture is poured into aseparatory funnel containing brine and extracted 4× with CH₂ Cl₂. Theorganic extracts were combined and dried over anhydrous Na₂ SO₄. Themixture was filtered and concentrated in vacuo. The triarylbismuthine isisolated and purified by flash column chromatography on silica gel.

EXAMPLE 14B

Tri(6-Methoxy-2-naphthyl)bismuth diacetate

To a stirred solution of tris(6-methoxy-naphth-2-yl)bismuthine (100 mg,0.158 mmol) in CH₂ Cl₂ (8 mL) was added iodobenzene diacetate (200 mg,0.621 mmol). The CH₂ Cl₂ was removed in vacuo and the residue wasdissolved in several milliliters of 4:1 hexanes/acetone plus smallamount of CH₂ Cl₂. The solution was passed through a silica gel plug andeluted with 4:1 hexanes/acetone. The filtrate was concentrated in vacuo.The residue was dissolved in 4:1 hexanes/acetone plus small amount ofCH₂ Cl₂ and passed through a second silica gel plug and eluted with 4:1hexanes/acetone. The filtrate was concentrated in vacuo leaving 52 mgyellow residue that was used without further purification.

EXAMPLE 15

A. 17-Ethyl-1,14-dihydroxy-12-2'-(3"-(6'"-methoxynaphth-2-yloxy)-4'-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone and

B. 17-Ethyl-1,14-dihydroxy-12-2'-(4"-(6'"-methoxynaphth-2-yloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

To a solution of tri-(6-methoxy-2-naphthyl)bismuth diacetate (22 mg,0.028 mmol, 1 eq) in methylene chloride (2 ml) in a 10 mL round bottomflask equipped with a stir bar was added 17-ethyl-1,14-dihydroxy-12-2'-(3",4"-dihydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (22 mg, 0.028 mmol, 1eq). To the reaction mixture was added a catalytic amount of Cu(OAc)₂(approximately 20 mg). The reaction flask was fitted with a refluxcondenser and the mixture was warmed to 40° C. After 1 hour the mixturewas cooled, diluted with saturated aqueous NaHCO₃ and extracted 4 timeswith CH₂ Cl₂. The organic extracts were combined, dried over anhydrousNa₂ SO₄, filtered and concentrated in vacuo. The product was isolated bypreparative thin layer chromatography on silica gel (eluted with 2:1hexanes/acetone) to give 7.1 mg of 17-ethyl-1,14-dihydroxy-12-2'-(4"-(6'"-methoxynaphth-2-yloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,-10,16-tetraone (R_(f) =0.35) and 9 mgof 17-ethyl-1,14-dihydroxy-12-2'-(3"-(6'"-methoxynaphth-2-yloxy)-4"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (R_(f) =0.28). (¹ H NMRand mass spectral analysis were consistent with the desired structures).

EXAMPLE 16

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(4'"-methoxyphenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

To a stirred solution of tris(4-methoxyphenyl)bismuthine (200 mg, 0.377mmol) in CH₂ Cl₂ (4 mL) was added bis(trifluoroacetoxy)iodobenzene (162mg, 0.377 mmol). The mixture was stirred 5 minutes, then passed througha silica gel plug and eluted with EtOAc. The eluant was concentrated invacuo. The residue was dissolved in CH₂ Cl₂ (4 mL) in a 50 mL roundbottom flask equipped with a magnetic stir bar. To this stirred mixturewas added 17-ethyl-1,14-dihydroxy-12-2'-(4"-hydroxy-3"-methoxycyclohexyl)-1"-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (132 mg, 0.167 mmol) andCu(OAc)₂ (10 mg 0.055 mmol). The flask was capped and the mixturestirred 48 hours. The reaction was quenched by addition of saturatedaqueous NaHCO₃ and extracted 4× with CH₂ C1₂. The organic extracts werecombined and dried over anhydrous Na₂ SO₄. The mixture was filtered andconcentrated in vacuo. The products were isolated by preparative TLC onsilica gel (2:1 hexanes/acetone) to afford 26.8 mg of17-ethyl-1,14-dihydroxy-12-2'-(4"-(4'"-methoxyphenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (R_(f) =0.35). (¹ H NMRand mass spectral analysis were consistent with the desired structure).

EXAMPLE 17

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(3'"-methoxyphenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

To a stirred solution of tris(3-methoxyphenyl)bismuthine (200 mg, 0.377mmol) in CH₂ Cl₂ (3 mL) was added bis(trifluoroacetoxy)iodobenzene (162mg, 0.377 mmol). The mixture was stirred 5 minutes, then passed througha silica gel plug and eluted with EtOAc. The eluant was concentrated invacuo. The residue was dissolved in CH₂ Cl₂ (4 mL) in a 50 mL roundbottom flask equipped with a magnetic stir bar. To this stirred mixturewas added 17-ethyl-1,14-dihydroxy-12-2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (112 mg 0.141 mmol) andCu(OAc)₂ (10 mg, 0.055 mmol). The flask was capped and the mixturestirred 48 hours. The reaction was quenched by addition of saturatedaqueous NaHCO₃ and extracted 4× with CH₂ Cl₂. The organic extracts werecombined and dried over anhydrous Na₂ SO₄. The mixture was filtered andconcentrated in vacuo. The products were isolated by radialchromatography on silica gel (2 mm plate eluted with 3:1hexanes/acetone) and then by preparative TLC on silica gel (eluted with2:1 hexanes/acetone) to afford 78.4 mg of 17-ethyl-1,14-dihydroxy-12-2'-(4"-(3'"-methoxyphenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (R_(f) =0.40). (¹ H NMRand mass spectral analysis were consistent with the desired structure).

EXAMPLE 18

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(6'"-tert-butyldimethylsilyloxynaphth-2-yloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

To a stirred solution oftris(6-tert-butyldimethylsilyloxynaphth-2-yl)bismuthine (100 mg, 0.215mmol) in CH₂ Cl₂ (4 mL) was added peracetic acid (0.05 mL, 0.238 mmol,32 wt % in dilute acetic acid). To this stirred solution was added THF(1 mL), 17-ethyl-1,14-dihydroxy-12-2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (100 mg, 0.126 mmol) andCu(OAc)₂ (catalytic amount). The flask was fitted with a refluxcondenser and the mixture was heated to 40° C. for 2 hours. The mixturewas allowed to cool and was stirred 72 hours. The reaction was quenchedwith saturated aqueous NaHCO₃ and extracted 4× with CH₂ Cl₂. The organicextracts were combined and dried over anhydrous Na₂ SO₄. The mixture wasfiltered and concentrated in vacuo. The products were isolated bypreparative TLC on silica gel (eluted with 2:1 hexanes/acetone) toafford 47 mg of 17-ethyl-1,14-dihydroxy-12-2'-(4"-(6'"-tert-butyldimethylsilyloxynaphth-2-yloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (R_(f) =0.56).

(¹ H NMR and mass spectral analysis were consistent with the desiredstructure).

EXAMPLE 19

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(6'"-hydroxynaphth-2-yloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

To a stirred solution of 17-ethyl-1,14-dihydroxy-12-2'-(4"-(6'"-tert-butyldimethylsilyloxynaphth-2-yloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (73 mg, 0.07 mmol) in CH₂Cl₂ (2 mL) was added a solution of p-toluenesulfonic acid in methanol (2mL, 10% solution). The flask was capped and the mixture stirred 4 hours.The reaction was quenched with saturated aqueous NaHCO₃ and extracted 4×with CH₂ Cl₂. The organic extracts were combined and dried overanhydrous Na₂ SO₄. The mixture was filtered and concentrated in vacuo.The product was isolated by preparative TLC on silica gel (eluted with2:1 hexanes/acetone) to afford 44.2 mg of 17-ethyl-1,14-dihydroxy-12-2'-(4"-(6'"-hydroxynaphth-2-yloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (R_(f) =0.23). (¹ H NMRand mass spectral analysis were consistent with the desired structure).

EXAMPLE 20

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(4'"-tert-butyldimethylsilyloxyphenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

To a stirred solution oftris(4-tert-butyldimethylsilyloxyphenyl)bismuthine (187 mg, 0.252 mmol)in CH₂ Cl₂ (4 mL) was added peracetic acid (0.053 mL, 0.252 mmol, 32 wt% solution in dilute acetic acid). To this stirred solution was added17-ethyl-1,14-dihydroxy-12-2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (100 mg, 0.126 mmol),Cu(OAc)₂ (8.5 mg, 0.046 mmol), and tetrahydrofuran (0.5 mL). Afterstirring 48 hours the reaction mixture was quenched with saturatedaqueous NaHCO₃ and extracted 4× with CH₂ Cl₂. The organic extracts werecombined and dried over anhydrous Na₂ SO₄. The mixture was filtered andconcentrated in vacuo. The products were isolated by prepamtive TLC onsilica gel (eluted with 2:1 hexanes/acetone) to afford 81 mg of17-ethyl-1,14-dihydroxy-12-2'-(4"-(4'"-tert-buytldimethylsilyloxyphenyloxy)-3"-methoxycyclo-hexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !-octacos-18-ne-2,3,10,16-tetraone (R_(f) =0.49). (¹ H NMRand mass spectral analysis were consistent with the desired structure).

EXAMPLE 21

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(4'"-hydroxyphenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

To a stirred solution of 17-ethyl-1,14-dihydroxy-12-2'-(4"-(4'"-tert-buytldimethylsilyloxyphenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (74.8 mg, 0.075 mmol) inCH₂ Cl₂ was added a solution of p-toluenesulfonic acid in methanol (2mL, 10% p-TsOH on methanol). The mixture was stirred 4 hours. Thereaction mixture was quenched with saturated aqueous NaHCO₃ andextracted 4× with CH₂ Cl₂. The organic extracts were combined and driedover anhydrous Na₂ SO₄. The mixture was filtered and concentrated invacuo. The products were isolated by preparative TLC on silica gel(eluted with 2:1 hexanes/acetone) to afford 52 mg of17-ethyl-1,14-dihydroxy-12-2'-(4"-(4'"-hydroxyphenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (R_(f) =0.25). (¹ H NMRand mass spectral analysis were consistent with the desired structure).

EXAMPLE 22

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(4'"-methylthiophenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

To a stirred solution of tris(4-methylthiophenyl)bismuthine (146 mg,0.252 mmol) in CH₂ Cl₂ was added peracetic acid (0.106 mL, 0.504 mmol).To this solution was added 17-ethyl-1,14-dihydroxy-12-2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (100 mg, 0.126 mmol),Cu(OAc)₂ (1 mg, 0.061 mmol), and tetrahydrofuran (0.5 mL). The mixturewas stirred for 96 hours. The reaction mixture was quenched withsaturated aqueous NaHCO₃ and extracted 4× with CH₂ Cl₂. The organicextracts were combined and dried over anhydrous Na₂ SO₄. The mixture wasfiltered and concentrated in vacuo. The products were isolated bypreparative TLC on silica gel (eluted with 2:1 hexanes/acetone) toafford 15.5 mg of 17-ethyl-1,14-dihydroxy-12-2'-(4"-(4'"-methylthiophenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (R_(f) =0.47). (¹ H NMRand mass spectral were analysis consistent with the desired structure).

EXAMPLE 23

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-methylphenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

To a stirred solution of tris(2-methylphenyl)bismuthine (50 mg, 0.104mmol) in CH₂ Cl₂ (2mL) was added bis(trifluoroacetoxy)iodobenzene (45mg, 0.104 mmol). To this stirred solution was added17-ethyl-1,14-dihydroxy-12-2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (82 mg, 0.104 mmol),Cu(OAc)₂ (catalytic), and acetic acid (0.060 mL, 0.104 mmol). The flaskwas fitted with a reflux condenser and the mixture warmed to 40° C. andstirred overnight. The reaction mixture was cooled and diluted with CH₂Cl₂. The reaction mixture was quenched with saturated aqueous NaHCO₃ andextracted 4× with CH₂ Cl₂. The organic extracts were combined and driedover anhydrous Na₂ SO₄. The mixture was filtered and concentrated invacuo. The products were isolated by preparative TLC on silica gel(eluted with 2:1 hexanes/acetone) to afford 23.8 mg of17-ethyl-1,14-dihydroxy-12-2'-(4'-(2'"-methylphenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (R_(f) =0.46). (¹ H NMRand mass spectral analysis were consistent with the desired structure).

EXAMPLE 24

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(3'"-methylphenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

To a stirred solution of tris(3-methylphenyl)bismuthine (189 mg, 0.392mmol) in CH₂ Cl₂ (3 mL) was added bis(trifluoro-acetoxy)iodobenzene (168mg, 0.392 mmol). To this stirred solution was added17-ethyl-1,14-dihydroxy-12-2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (150 mg, 0.189 mmol) andCu(OAc)₂ (catalytic). The flask was capped and the mixture stirredovernight. The reaction mixture was quenched with saturated aqueousNaHCO₃ and extracted 4× with CH₂ Cl₂. The organic extracts were combinedand dried over anhydrous Na₂ SO₄. The mixture was filtered andconcentrated in vacuo. The products were isolated by radialchromatography on silica gel (eluted with 3:1 hexanes/ethyl acetate) toafford 70.9 mg of 17-ethyl-1,14-dihydroxy-12-2'-(4"-(3'"-methylphenyloxy)-3"-methoxycyclohexyl)-1'-methyl-vinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone. (¹ H NMR and massspectral analysis were consistent with the desired structure).

EXAMPLE 25

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(3'",4'"-dimethylphenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

To a stirred solution of tris(3,4-dimethylphenyl)bismuthine (200 mg,0.381 mmol) in CH₂ Cl₂ (3 mL) was added bis(trifluoroacetoxy)iodobenzene(165 mg, 0.383 mmol). One mL of this solution was transferred to a 10 mLflask. To this solution was added 17-ethyl-1,14-dihydroxy-12-2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (100 mg, 0.128 mmol) andCu(OAc)₂ (catalytic). The mixture was stirred overnight. The reactionmixture was quenched with saturated aqueous NaHCO₃ and extracted 4× withCH₂ Cl₂. The organic extracts were combined and dried over anhydrous Na₂SO₄. The mixture was filtered and concentrated in vacuo. The productswere isolated by radial chromatography on silica gel (eluted with 3.5%methanol/CH₂ Cl₂) and then purified by preparative TLC on silica gel(eluted with 3:1 hexanes/acetone) to afford 24.3 mg of17-ethyl-1,14-dihydroxy-12-2'-(4"-(3'",4'"-dimethylphenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone. (¹ H NMR and massspectral analysis were consistent with the desired structure).

EXAMPLE 26

A. 17-Ethyl-1,14-dihydroxy-12-2'-(3"-(4'"-methoxyphenyloxy)-4"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone and

B. 17-Ethyl-1,14-dihydroxy-12-2'-(4"-(4'"-methoxyphenyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

To a stirred solution of tri(4-methoxyphenyl)bismuthine (136 mg, 0.257mmol, 2 eq.) in methylene chloride (4 mL) was added peracetic acid(0.054 mL, 0.257 mmol, 2 eq, 32% solution in dilute acetic acid). Tothis stirred solution was added 17-ethyl-1,14-dihydroxy-12-2'-(3",4"-dihydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (100 mg, 0.126 mmol, 1eq), THF (0.5 mL), and copper (II) acetate (7 mg, 0.038 mmol, 0.3 eq).The mixture was allowed to stir for 7 days. The reaction was quenchedwith saturated aqueous NaCl plus 2 drops 2N HCl and extracted 4× withmethylene chloride. The organic extracts were combined, dried overanhydrous Na₂ SO₄, filtered, and concentrated in vacuo. The productswere separated by preparative TLC on silica gel (2:1 hexanes/acetone).Each compound was repurified 2× by preparative TLC on silica gel (3:1hexanes/acetone then 3.5% MeOH/CH₂ Cl₂) affording 23.4 mg of17-ethyl-1,14-dihydroxy-12-2'-(4"-(4'"-methoxyphenyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-22.3.1.0⁴,9!octacos-18-ene-2,3,10,16-tetraone and 28.4 mg of17-ethyl-1,14-dihydroxy-12-2'-(3"-(4'"-methoxyphenyloxy)-4"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone. (¹ H NMR and massspectral analysis were consistent with the desired structures).

EXAMPLE 27

A. 17-Ethyl-1,14-dihydroxy-12-2'-(3"-(3'"-methoxyphenyloxy)-4"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone and

B. 17-Ethyl-1,14-dihydroxy-12-2'-(4"-(3'"-methoxyphenyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatridcyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

To a stirred solution of tri(3-methoxyphenyl)bismuthine (136 mg, 0.257mmol, 2 eq) in methylene chloride (4 mL) was added peracetic acid (0.054mL, 0.257 mmol, 2 eq, 32% solution in dilute acetic acid). To thisstirred solution was added 17-ethyl-1,14-dihydroxy-12-2'-(3",4"-dihydroxycyclohexyl)-1'-methylvinyl!23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (100 mg, 0.126 mmol, 1eq), THF (0.5 mL), and copper (II) acetate (7 mg, 0.038 mmol, 0.3 eq).The mixture was allowed to stir for 7 days. The reaction was quenchedwith saturated aqueous NaCl plus 2 drops 2N HCl and extracted 4× withmethylene chloride. The organic extracts were combined, dried overanhydrous Na₂ SO₄, filtered, and concentrated in vacuo. The productswere separated by preparative TLC on silica gel (2:1 hexanes/acetone).Each compound was repurified 2× by preparative TLC on silica gel (2:1hexanes/acetone then 3.5% MeOH/CH₂ Cl₂) affording 27 mg of17-ethyl-1,14-dihydroxy-12-2'-(4"-(3'"-methoxyphenyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone and 35 mg of17-ethyl-1,14-dihydroxy-12-2'-(3"-(3'"-methoxyphenyloxy)-4"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone. (¹ H NMR and massspectral analysis were consistent with the desired structures).

EXAMPLE 28

A. 17-Ethyl-1,14-dihydroxy-12-2'-(3"-(4'"-tert-butyldimethylsilyloxyphenyloxy)-4"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos -18-ene-2,3,10,16-tetraone and

B. 17-Ethyl-1,14-dihydroxy-12-2'-(4"-(4'"-tert-butyldimethylsilyloxyphenyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

To a stirred solution oftri(4-tert-butyldimethylsilyloxyphenyl)bismuthine (213 mg, 0.257 mmol, 2eq) in methylene chloride (4 mL) was added peracetic acid (0.054 mL,0.257 mmol, 2 eq, 32% solution in dilute acetic acid). To this stirredsolution was added 17-ethyl-1,14-dihydroxy-12-2'-(3",4"-dihydroxycyclohexyl)-1'-methyl-vinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (100 mg, 0.126 mmol, 1eq), THF (0.5 mL), and copper (II) acetate (7 mg, 0.038 mmol, 0.3 eq).The mixture was allowed to stir for 7 days. The reaction was quenchedwith saturated aqueous NaCl plus 2 drops 2N HCl and extracted 4× withmethylene chloride. The organic extracts were combined, dried overanhydrous Na₂ SO₄, filtered, and concentrated in vacuo. The productswere separated by preparative TLC on silica gel (2:1 hexanes/acetone)affording 41.9 mg of 17-ethyl-1,14-dihydroxy-12-2'-(4"-(4'"-tert-butyldimethylsilyloxyphenyloxy)-3"-hydroxy-cyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone and 42.5 mg. of17-ethyl-1,14-dihydroxy-12-2'-(3"-(4'"-tert-butyldimethylsilyloxyphenyloxy)-4"-hydroxycyclo-hexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone. (¹ H NMR and massspectral analysis were consistent with the desired structures).

EXAMPLE 29

17-Ethyl-1,14-dihydroxy-12-2'-(3"-(4'"-hydroxyphenyloxy)-4"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

To a stirred solution of 17-ethyl-1,14-dihydroxy-12-2'-(3"-(4'"-tert-butyldimethylsilyloxyphenyloxy)-4"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (42.5 mg) in CH₂ Cl₂ (1.5mL) at 0° C. was added a solution of p-toluenesulfonic acid in methanol(1.5 mL of a 10% w/v solution). The mixture was stirred 3H at 0° C. andthen 3H at room temperature. The reaction mixture was quenched withsaturated aqueous NaHCO₃ and extracted 4× with CH₂ Cl₂. The organicextracts were combined and dried over anhydrous Na₂ SO₄. The mixture wasfiltered and concentrated in vacuo. The product was isolated bypreparative TLC on silica gel (eluted with 2:1 hexanes/acetone)affording 25.7 mg of 17-ethyl-1,14-dihydroxy-12-2'-(3"-(4'"-hydroxyphenyloxy)-4"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone. (¹ H NMR and massspectral analysis were consistent with the desired structure).

EXAMPLE 30

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(4'"-hydroxyphenyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

To a stirred solution of 17-ethyl-1,14-dihydroxy-12-2'-(4"-(4'"-tert-butyldimethylsilyloxyphenyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (41.9 mg) in CH₂ Cl₂ (1.5mL) at 0° C. was added a solution of p-toluenesulfonic acid in methanol(1.5 mL of a 10% w/v solution). The mixture was stirred 3H at 0° C. andthen 3H at room temperature. The reaction mixture was quenched withsaturated aqueous NaHCO₃ and extracted 4× with CH₂ Cl₂. The organicextracts were combined and dried over anhydrous Na₂ SO₄. The mixture wasfiltered and concentrated in vacuo. The product was isolated bypreparative TLC on silica gel (eluted with 2:1 hexanes/acetone)affording 23.9 mg of 17-ethyl-1,14-dihydroxy-12-2'-(4"-(4'"-hydroxyphenyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone. (¹ H NMR and massspectral analysis are consistent with the desired structure).

EXAMPLE 31

A. 17-ethyl-1,14-dihydroxy-12-2'-(3"-(6'"-tert-butyldimethylsilyloxynaphth-2-yloxy)-4"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone and17-Ethyl-1,14-dihydroxy-12-2'-(4"-(6'"-tert-butyldimethylsilyloxynaphth-2-yloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

To a stirred solution oftri(6-tert-butyldimethylsilyloxynaphth-2-yl)bismuthine (252 mg, 0.257mmol, 2 eq) in methylene chloride (4 mL) was added peracetic acid (0.054mL, 0.257 mmol, 2 eq, 32% solution in dilute acetic acid). To thisstirred solution was added 17-ethyl-1,14-dihydroxy-12-2'-(3",4"-dihydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (100 mg, 0.126 mmol, 1eq), THF (0.5 mL ), and copper (II) acetate (7 mg, 0.038 mmol, 0.3 eq).The mixture was allowed to stir for 7 days. The reaction was quenchedwith saturated aqueous NaCl plus 2 drops 2N HCl and extracted 4× withmethylene chloride. The organic extracts were combined, dried overanhydrous Na₂ SO₄, filtered, and concentrated in vacuo. The productswere separated by preparative TLC on silica gel (2:1 hexanes/acetone)affording 39.8 mg of 17-ethyl-1,14-dihydroxy-12-2'-(4"-(6'"-tert-butyldimethylsilyloxynaphth-2-yloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone and 41.6 mg. of17-ethyl-1,14-dihydroxy-12-2'-(3"-(6'"-tert-butyldimethylsilyloxynaphth-2-yl-oxy)-4"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone. (¹ H NMR and massspectral analysis were consistent with the desired structures).

EXAMPLE 32

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(6'"-hydroxynaphth-2-yloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

To a stirred solution of 17-ethyl-1,14-dihydroxy-12-2'-(4"-(6'"-tert-butyldimethylsilyloxynaphth-2-yloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (39.8 mg) in CH₂ Cl₂ (1.5mL) at 0° C. was added a solution of p-toluenesulfonic acid in methanol(1.5 mL of a 10% w/v solution). The mixture was stirred 1.25 h at 0° C.and then 1.75 h at room temperature. The reaction mixture was quenchedwith saturated aqueous NaHCO₃ and extracted 4× with CH₂ Cl₂. The organicextracts were combined and dried over anhydrous Na₂ SO₄. The mixture wasfiltered and concentrated in vacuo. The product was isolated bypreparative TLC on silica gel (eluted 2× with 2:1 hexanes/acetone)affording 17 mg of 17-ethyl-1,14-dihydroxy-12-2'-(4"-(6'"-hydroxynaphth-2-yloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone. (¹ H NMR and massspectral analysis were consistent with the desired structure).

EXAMPLE 33

17-Ethyl-1,14-dihydroxy-12-2'-(3"-(6'"-hydroxynaphth-2-yloxy)-4"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

To a stirred solution of 17-ethyl-1,14-dihydroxy-12-2'-(3"-(6'"-tert-butyldimethylsilyloxynaphth-2-yloxy)-4"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (41.6 mg) in CH₂ Cl₂ (1.5mL) at 0° C. was added a solution of p-toluenesulfonic acid in methanol(1.5 mL of a 10% w/v solution). The mixture was stirred 1.25 h at 0° C.and then 1.75 h at room temperature. The reaction mixture was quenchedwith saturated aqueous NaHCO₃ and extracted 4× with CH₂ Cl₂. The organicextracts were combined and dried over anhydrous Na₂ SO₄. The mixture wasfiltered and concentrated in vacuo. The product was isolated bypreparative TLC on silica gel (eluted 2× with 2:1 hexanes/acetone)affording 20.8 mg of 17-ethyl-1,14-dihydroxy-12-2'-(3"-(6'"-hydroxynaphth-2-yloxy)-4"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone. (¹ H NMR and massspectral analysis were consistent with the desired structure).

EXAMPLE 34

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(ethoxycarbomethoxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

To a stirred solution of 17-ethyl-1,14-dihydroxy-12-2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (200 mg, 0.253 mmol, 1eq) in diethyl ether (6 mL) was added boron trifluoride etherate (0.009mL, 0.073 mmol, 0.3 eq) and ethyl diazoacetate (0.080 mL, 0.760 mmol, 3eq). The reaction mixture was stirred 12 h. The reaction mixture wasquenched with saturated aqueous NaHCO₃ and extracted 4× with CH₂ Cl₂.The organic extracts were combined and dried over anhydrous Na₂ SO₄. Themixture was filtered and concentrated in vacuo. The products wereisolated by preparative TLC on silica gel (3:2 EtOAc/hexanes) and asecond preparative TLC (eluted 2× with 3:1 hexanes/acetone) affording24.7 mg of 17-ethyl-1,14-dihydroxy-12-2'-(4"-(ethoxycarbomethoxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone. (¹ H NMR, ¹³ C NMR andmass spectral analysis were consistent with the desired structure).

EXAMPLE 35

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(3'",4'"-dichlorophenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

To a stirred solution of tri(3,4-dichlorophenyl)bismuthine (163 mg, 0.25mmol) in CH₂ Cl₂ (2 mL) was added bis(trifluoroacetoxy)iodobenzene (107mg, 0.25 mmol). The mixture was stirred for 15 minutes then treated withCu(OAc)₂ followed by a solution of 17-ethyl-1,14-dihydroxy-12-2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (100 mg, 0.126 mmol) inCH₂ Cl₂ (2 mL). After stirring an additional 2 hours the reactionmixture was quenched by addition of saturated aqueous NaHCO₃ andextracted 2× with CH₂ Cl₂. The organic extracts were combined, driedover anhydrous Na₂ SO₄, filtered, and concentrated in vacuo. The productwas separated and purified by preparative TLC on silica (eluted with 3:1Hexane/Acetone) to give 51 mg 17-ethyl-1,14-dihydroxy-12-2'-(4"-(3'",4'"-dichlorophenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (¹ H NMR, ¹³ H NMR, andmass spectral analysis are consistent with the desired structure).

EXAMPLE 36

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(phenanthr-9-yl)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

To a stirred solution of tri(9-phenanthryl)bismuthine (150 mg, 0.20mmol) in CH₂ Cl₂ (3 mL) was added peracetic acid (0.050 mL, 0.22 mmol,32 wt % solution in dilute acetic acid). After 15 minutes the solutionwas treated with 17-ethyl-1,14-dihydroxy-12-2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (100 mg, 0.126 mmol) andCu(OAc)₂ (10 mg, 0.055 mmol) and stirred for 18 hours. The reactionmixture was quenched with saturated aqueous NaHCO₃ and extracted 3× withCH₂ Cl₂. The extracts were combined, dried with Na₂ SO₄, filtered andconcentrated in vacuo. The product was isolated and purified bypreparative TLC on silica gel (eluted with 2:1 hexane/acetone to give 12mg of 17-ethyl-1,14-dihydroxy-12-2'-(4"-(phenanthr-9-yl)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (¹ H NMR was consistentwith the desired structure).

EXAMPLE 37

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(3'",4'"-methylenedioxyphenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

To a stirred solution of tri(3,4-methylenedioxyphenyl)bismuthine (150mg, 0.26 mmol) in CH₂ Cl₂ (2 mL) was added peracetic acid (0.060 mL,0.26 mmol, 32 wt % solution in dilute acetic acid). After approximately10 minutes the solution was treated with Cu(OAc)₂ (25 mg, 0.138 mmol)and 17-ethyl-1,14-dihydroxy-12-2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (100 mg, 0.126 mmol) andstirred for 18 hours. The reaction mixture was quenched with saturatedaqueous NaHCO₃ and extracted 2× with CH₂ Cl₂. The extracts werecombined, dried with anhydrous Na₂ SO₄, filtered, and concentrated invacuo. The product was isolated and purified by preparative TLC onsilica gel (eluted with 2:1 Hexane/Acetone) to give 37 mg of17-ethyl-1,14-dihydroxy-12-2'-(4"-(3'",4'"-methylenedioxyphenyloxy)-3"-methoxy-cyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (¹ H NMR and massspectral analysis were consistent with the desired structure).

EXAMPLE 38

17-Ethyl-1,14-dihydroxy-12- 2'-(4"-(2'",3'"-dihydrobenzofuran-5-yl)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

To a stirred solution of tri(2,3-dihydrobenzofuran-5-yl)bismuthine (32mg, 0.056 mmol) in CH₂ Cl₂ (1 mL) was added peracetic acid (0.020 mL,0.09 mmol, 32 wt % solution in dilute acetic acid). After approximately15 minutes the solution was treated with Cu(OAc)₂ (20 mg, 0.11 mmol) and17-ethyl-1,14-dihydroxy-12-2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (50 mg, 0.06 mmol) andstirred for three days. The reaction mixture was quenched with saturatedaqueous NaHCO₃ and extracted with CH₂ Cl₂. The extracts were combined,dried with anhydrous Na₂ SO₄, filtered and concentrated in vacuo. Theproduct was purified by preparative TLC on silica gel (eluted with 2:1Hexane/Acetone) to give 14 mg of 17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'",3'"-dihydrobenzofuran-5-yl)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricycio22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone characterized by (¹ H NMRand mass spectral analysis were consistent with the desired structure).

EXAMPLE 39

17-Allyl-1,14-dihydroxy-12-2'-(4"-(naphth-2-yl)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

A mixture of 17-allyl-1,14-dihydroxy-12-2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (400 mg, 0.5 mmol) andCu(OAc)₂ (35 mg, 0.19 mmol) in CH₂ Cl₂ (6 mL) was warmed to 40° C. for15 minutes then treated with tri(2-naphthyl)bismuth diacetate preparedimmediately prior to use by addition of acetic acid (0.18 mL, 3 mmol) toa suspension of tri(2-naphthyl)bismuth carbonate (600 mg, 0.92 mmol) inCH₂ Cl₂ (6 mL)!. Heating was maintained for 4 hours after which time themixture was stirred at room temperature for 18 hours. The reactionmixture was quenched with saturated aqueous NaHCO₃ and extracted withCH₂ Cl₂. The extracts were combined, dried with Na₂ SO₄, filtered andconcentrated in vacuo. The product was isolated and purified bypreparative TLC on silica gel (eluted with 3:1 Hexane/Acetone) to give234 mg of 17-allyl-1,14-dihydroxy-12-2'-(4"-(naphth-2-yl)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (¹ H NMR and massspectral analysis were consistent with the desired structure).

EXAMPLE 40

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(1'",4'"-benzodioxane-6-yl)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

To a stirred solution of tris(1,4-benzodioxan-6-yl)bismuthine (90 mg,0.146 mmol) in CH₂ Cl₂ (1 mL) was added peracetic acid (0.030 mL, 0.13mmol, 32 wt % in dilute acetic acid). After 20 minutes the mixture wastreated with 17-ethyl-1,14-dihydroxy-12- 2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (100 mg, 0.126 mmol)followed by Cu(OAc)₂ (15 mg, 0.08 mmol) and stirred for 2 days. Thereaction mixture was quenched with saturated aqueous NaHCO₃ andextracted with CH₂ Cl₂. The extracts were combined, dried with Na₂ SO₄,filtered and concentrated in vacuo. The product was purified bypreparative TLC on silica gel (eluted with 4% CH₃ OH in CH₂ Cl₂) to give18 mg of 17-ethyl-14-dihydroxy-12-2'-(4"-(1'",4'"-benzodioxane-6-yl)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (¹ H NMR and massspectral analysis were consistent with the desired structure).

EXAMPLE 40B

17-Ethyl-1-hydroxy-12-2'-(4"-(4'"-dimethylamino)-phenyloxy-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !-octacos-18-ene-2,3,10,16-tetraone (A) and

17-Ethyl-1-hydroxy-12-2'-(4"-hydroxy-3"-(4'"-dimethylamino)-phenyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !-octacos-18-ene-2,3,10,16-tetraone (B)

Peracetic acid (850 ml) was added to a solution oftri(4-dimethylaminophenyl)bismuthine (1.27 g) in 30 ml tetrahydrofuran.After 10 minutes 17-ethyl-1-hydroxy-12-2'-(3",4"-dihydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0.sup.4,9 !-octacos-18-ene-2,3,10,16-tetraone (100 mg) was addedfollowed by copper acetate (280 mg) and the mixture heated to 60° C. for48 hours. The mixture was then cooled and quenched by pouring intosaturated sodium bicarbonate, extracting with ether (3×25 ml). Thecombined organic washes were dried with magnesium sulphate andconcentrated. The crude residue was purified by column chromatography onsilica gel eluting with 70% hexane:30% ethyl acetate to give the titleCompounds A (93 mg) and B (102 mg) each as white solids.

EXAMPLE 41

17-Ethyl-1,2,14-trihydroxy-12-2'-(4"-(naphth-2-yl)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-3,10,16-trione

A solution of 1,2-diiodoethane (42 mg, 0.15 mmol) in dry THF (1 mL) wasadded dropwise to a stirred mixture of samarium metal (46.5 mg, 0.31mmol) in dry THF (1 mL) and stirred for 1.5 hours. The reaction mixturewas then cooled to -78° C. (dry ice/acetone) and treated with a solutionof 17-ethyl-1,14-dihydroxy-12-2'-(4"-(naphth-2-yl)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (100 mg, 0.109 mmol) in1:1 THF/CH₃ OH. The mixture was maintained at -78° C. for 15 minutesthen allowed to warm to room temperature. The reaction was quenched withcold saturated aqueous K₂ CO₃ and quickly extracted with CH₂ Cl₂. Theextracts were combined, dried with Na₂ SO₄, filtered and concentrated invacuo. Purified by preparative TLC on silica gel (eluted with 7% CH₃ OHin CH₂ Cl₂) to give 22 mg of 17-ethyl-1,2,14-trihydroxy-12-2'-(4"-(naphth-2-yl)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-22.3.1.0⁴,9 !octacos-18-ene-3,10,16-trione (¹ H NMR and mass spectralanalysis are consistent with the desired structure).

EXAMPLE 42

17-Ethyl-1,14-dihydroxy-12-2'-(4"-allyloxy-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

To a solution of 17-ethyl-1,14-dihydroxy-12-2'-(4"-hydroxy-3"-methoxycyclohexyl)-1"-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (200 mg in 3.0 ml 33%methylene chloride in cyclohexane), allyl trichloroacetimidate (88 μlneat) was added and the reagents allowed to mix for 5 minutes.Trifluoromethanesulfonic acid (4.5 μl neat) was added slowly via syringeand the mixture stirred at room temperature. After 18 hours the reactionwas quenched by the addition of saturated sodium bicarbonate andextracted with ethyl acetate (3×5 ml). The combined organics were washedwith brine and dried over magnesium sulfate. Purification of theconcentrate by flash chromatography on silica gel (ethyl acetate:hexane(1:2)+1% methanol) gave the title compound (156 mg).

MASS: (FAB) 838 (M+Li)

Partial ¹ H NMR δ: 5.82 (m, 1H); 4.85 (m), 4.20 (brs, 1H); 4.59 (brdJ=4.5 Hz, 1H); 4.41 (brd J=14 Hz, 1H); 4.03 (dt J=4.0, 1.0 Hz, 2H).

EXAMPLE 43

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(2-butynyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

To a solution of 17-ethyl-1,14-dihydroxy-12-2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (50 mg in 1.5 ml 33%methylene chloride in cyclohexane), 2-butynyl trichloroacetimidate (20μl neat) was added and the reagents allowed to mix for 5 minutes.Trifluoromethanesulfonic acid (2 μl neat) was added slowly via syringeand the mixture stirred at room temperature. After 16 hours the reactionwas quenched by the addition of saturated sodium bicarbonate andextracted with ethyl acetate (3×5 ml). The combined organics were washedwith brine and dried over magnesium sulfate. Purification of theconcentrate by preparative TLC on silica gel (ethyl acetate:hexane(1:1)+1% methanol) gave the title compound (17 mg).

MASS: (FAB) 843 (M+Na)

Partial ¹ H NMR δ: 5.32(Major amide rotamer), 5.29(minor amide rotamer)(brd J=3.0 Hz, 1H); 4.83m, 4.21M (brs, 1H); 4.59 (brd J=4.0 Hz, 1H);4.42 (brd J=14.0 Hz, 1H); 4.26 (m, 2H); 1.83 (t J=2.0 Hz,3H).

EXAMPLE 44

17-Ethyl-1,14-dihydroxy-12-2'-(4"-cinnamyloxy-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

To a solution of 17-ethyl-1,14-dihydroxy-12-2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl!23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (50 mg in 1.5 ml 33%methylene chloride in cyclohexane), cinnamyl trichloroacetimidate (26 μlneat) was added and the reagents allowed to mix for 5 minutes.Trifluoromethanesulfonic acid (2 μl neat) was added slowly via syringeand the mixture stirred at room temperature. After 15 minutes thereaction was quenched by the addition of saturated sodium bicarbonateand extracted with ethyl acetate (3×5 ml). The combined organics werewashed with brine and dried over magnesium sulfate. Purification of theconcentrate by preparative TLC on silica gel (ethyl acetate:hexane(1:1)+1% methanol) gave the title compound (10 mg).

MASS: (FAB) 907 (M+Na)

Partial ¹ H NMR δ: 6.62 (d J=15 Hz, 1H); 6.30 (dt J=15, 6.0 Hz, 1H);5.33M, 5.19m (brd J=3.0 Hz, 1H); 4.83m, 4.21M (brs, 1H); 4.58 (brd J=4.0Hz, 1H); 4.41 (brd J=14 Hz, 1H); 4.30 (d J=6.0 Hz, 2H).

EXAMPLE 45

17-Ethyl-1,14-dihydroxy-12-2'-(3"-methoxy-4"-phenylpropyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

To a solution of 17-ethyl-1,14-dihydroxy-12-2'-(4"-cinnamyloxy-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (37 mg in 2 ml ethanol)was added 4 mg of 5% rhodium on carbon catalyst. The reaction flask wasfitted with a hydrogen balloon, evacuated and recharged with hydrogen (3times) and stirred at room temperature. After 1.5 hours, the mixture wasfiltered over Celite, concentrated and purified by preparative TLC onsilica gel (ethyl acetate:hexane (1:2)+1% methanol) to give the titlecompound (19.5 mg).

MASS: (FAB) 932 (M+Na); 916 (M+Li)

Partial ¹ H NMR δ: 5.31M, 5.28m (d J=3.0 Hz, 1H); 4.85m, 4.21M (brs,1H); 4.58 (brd J=4.0 Hz, 1H); 4.41 (brd J=14 Hz, 1H); 2.69 (t J=8.0 Hz,2H).

EXAMPLE 46

A. 7-Ethyl-1,14-dihydroxy-12-2'-(4"-allyloxy-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone and

B. 17-Ethyl-1,14-dihydroxy-12-2'-(3"-allyloxy-4"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

To a solution of 17-ethyl-1,14-dihydroxy-12-2'-(3",4"-dihydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (100 mg in 1.5 ml 33%methylene chloride in cyclohexane), allyl trichloroacetimidate (53 μlneat) was added and the reagents allowed to mix for 5 minutes.Trifluoromethanesulfonic acid (2 μl neat) was added slowly via syringeand the mixture stirred at room temperature. After 3 hours the reactionwas quenched by the addition of saturated sodium bicarbonate andextracted with ethyl acetate (3×5 ml). The combined organics were washedwith brine and dried over magnesium sulfate. Purification of theconcentrate by flash chromatography on silica gel (ethyl acetate:hexane(1:1)+1% methanol) gave the title compounds (21 mg 4"-ether; 17 mg3"-ether).

A. (4"-ether)

Partial ¹ H NMR δ: 5.93 (m, 1H); 4.87m, 4.19M (brs, 1H); 4.59 (brd J=4.0Hz, 1H); 4.41 (brd J=14 Hz, 1H); 2.67 (brd J=3.7 Hz, 1H).

B. (3"-ether)

Partial ¹ H NMR δ: 5.93 (m, 1H); 4.83m, 4.23M (brs, 1H); 4.59 (brd J=4.0Hz, 1H); 4.41 (brd J=14 Hz, 1H); 2.63 (brs, 1H).

EXAMPLE 47

A. 17-Ethyl-1,14-dihydroxy-12-2'-(3"-hydroxy-4"-isopropoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone and

B. 17-Ethyl-1,14-dihydroxy-12-2'-(4"-hydroxy-3"-isopropoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

To a solution of 17-ethyl-1,14-dihydroxy-12-2'-(3",4"-dihydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (110 mg in 1.5 ml 33%methylene chloride in cyclohexane), isopropyl trichloroacetimidate (52μl neat) was added and the reagents allowed to mix for 5 minutes.Trifluoromethanesulfonic acid (2 μl neat) was added slowly via syringeand the mixture stirred at room temperature. After 3 hours the reactionwas quenched by the addition of saturated sodium bicarbonate andextracted with ethyl acetate (3×5 ml). The combined organics were washedwith brine and dried over magnesium sulfate. Purification of theconcentrate by preparative TLC on silica gel (ethyl acetate:hexane(1:1)+1% methanol) gave the title compounds (15 mg 4"-ether; 16 mg3"-ether).

A. (4"-ether)

MASS: (FAB) 826 (M+Li)

Partial ¹ H NMR δ: 5.31 (d J=3.0 Hz, 1H); 4.85m, 4.18M (brs, 1H); 4.58(brd J=4.0 Hz, 1H); 4.40 (brd J=14 Hz, 1H); 2.63 (brs, 1H).

B. (3"-ether)

MASS: (FAB) 826 (M+Li)

Partial ¹ H NMR δ: 5.31 (d J=3.0 Hz, 1H); 4.81m, 4.22M (brs, 1H); 4.58(brd J=4.0 Hz,1H); 4.40 (brd J=14 Hz, 1H); 2.60 (brs, 1H).

EXAMPLE 48

A. 17-Ethyl-1,14-dihydroxy-12-2'-(4"-sec-butenyloxy-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone and

B. 17-Ethyl-1,14-dihydroxy-12-2'-(3"-sec-butenyloxy-4"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

To a solution of 17-ethyl-1,14-dihydroxy-12-2'-(3",4"-dihydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (150 mg in 3 ml 33%methylene chloride in cyclohexane), sec-butenyl trichloroacetimidate (62μl neat) was added and the reagents allowed to mix for 5 minutes.Trifluoromethanesulfonic acid (2 μl neat) was added slowly via syringeand the mixture stirred at room temperature. After 15 minutes thereaction was quenched by the addition of saturated sodium bicarbonateand extracted with ethyl acetate (3×8 ml). The combined organics werewashed with brine and dried over magnesium sulfate. Purification of theconcentrate by preparative TLC on silica gel (ethyl acetate:hexane(1:1)+1% methanol) gave the title compounds (11 mg 4"-ether; 13 mg3"-ether).

A. (4"-ether)

MASS: (FAB) 831 (M+Na)

Partial ¹ H NMR δ: 5.65 (m, 1H); 5.32 (brd J=3.0 Hz, 1H); 4.87m, 4.1 8M(brs, 1H); 4.58 (brd J=4.0 Hz, 1H); 4.41 (brd J=14 Hz, 1H).

B. (3"-ether)

MASS: (FAB) 831 (M+Na)

Partial ¹ H NMR δ: 5.65 (m, 1H); 5.31 (brs, 1H); 4.82m, 4.22M (brs, 1H);4.58 (brd J=4.0 Hz, 1H); 4.41 (brd J=14 Hz, 1H).

EXAMPLE 49

A. 17-Ethyl-1,14-dihydroxy-12-2'-(4"-(trans-2'"-butenyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone and

B. 17-Ethyl-1,14-dihydroxy-12-2'-(3"-(trans-2'"-butenyloxy)-4"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

To a solution of 17-ethyl-1,14-dihydroxy-12-2'-(3",4"-dihydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (115 mg in 3 ml 33%methylene chloride in cyclohexane), trans-2-butenyl trichloroacetimidate(48 μl neat) was added and the reagents allowed to mix for 5 minutes.Trifluoromethanesulfonic acid (2 μl neat) was added slowly via syringeand the mixture stirred at room temperature. After 35 minutes thereaction was quenched by the addition of saturated sodium bicarbonateand extracted with ethyl acetate (3×8 ml). The combined organics werewashed with brine and dried over magnesium sulfate. Purification of theconcentrate by preparative TLC on silica gel (ethyl acetate:hexane(1:1)+1% methanol) gave the title compounds (14 mg 4"-ether; 12 mg3"-ether).

A. (4"-ether)

MASS: (FAB) 831 (M+Na)

Partial ¹ H NMR δ: 5.65(m, 1H); 5.31 (brd J=3.0 Hz, 1H); 4.86m, 4.19M(brs, 1H); 4.59 (brd J=4.0 Hz, 1H); 4.41 (brd J=14 Hz, 1H); 2.68 (brs,1H).

B. (3"-ether)

MASS: (FAB) 831 (M+Na)

Partial ¹ H NMR δ: 5.65 (m, 1H); 5.30 (brs, 1H); 4.81m, 4.22M (brs, 1H);4.59 (brd J=4.0 Hz, 1H); 4.41 (brd J=14 Hz, 1H); 2.64 (brs, 1H).

EXAMPLE 50

A. 17-Ethyl-1,14-dihydroxy-12-2'-(3"-hydroxy-4"-(3'"-methyl-2-butenyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone and

B. 7-Ethyl-1,14-dihydroxy-12-2'-(4"-hydroxy-3"-(3'"-methyl-2-butenyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

To a solution of 17-ethyl-1,14-dihydroxy-12-2'-(3",4"-dihydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (100 mg in 2 ml methylenechloride), 3-methyl-2-butenyl trichloroacetimidate (39 μl neat) wasadded and the reagents allowed to mix for 5 minutes. Camphorsulfonicacid (5 mg) was added and the mixture stirred at room temperature. After21 hours the reaction was quenched by the addition of saturated sodiumbicarbonate and extracted with ethyl acetate (3×8 ml). The combinedorganics were washed with brine and dried over magnesium sulfate.Purification of the concentrate by preparative TLC on silica gel (ethylacetate:hexane (1:1)+1% methanol) gave the title compounds (24 mg4"-ether; 21 mg 3"- ether).

A. (4"-ether)

MASS: (FAB) 845 (M+Na)

Partial ¹ H NMR δ: 4.87m, 4.19M (brs, 1H); 4.58 (brd J=4.0 Hz, 1H); 4.41(brd J=14 Hz, 1H); 2.70 (brs, 1H); 1.75 (s, 3H); 1.67 (s, 3H).

B. (3"-ether)

MASS: (FAB) 845 (M+Na)

Partial ¹ H NMR δ: 4.82m, 4.23M (brs, 1H);4.58 (brd J=4.0 Hz, 1H); 4.41(brd J=14 Hz, 1H); 2.67 (brs, 1H); 1.75 (s,3H); 1.67 (s, 3H).

EXAMPLE 51

A. 17-Ethyl-1,14-dihydroxy-12-2'-(3"-hydroxy-4"-(2'"-methylpropenyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone and

B. 17-Ethyl-1,14-dihydroxy-12-2'-(4"-hydroxy-3"-(2'"-methylpropenyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

To a solution of 17-ethyl-1,14-dihydroxy-12-2'-(3",4"-dihydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (200 mg in 3 ml 33%methylene chloride in cyclohexane), 2-methylpropenyltrichloroacetimidate (84 μl neat) was added and the reagents allowed tomix for 5 minutes. Trifluoromethanesulfonic acid (2 μl neat) was addedslowly via syringe and the mixture stirred at room temperature. After 1hour the reaction was quenched by the addition of saturated sodiumbicarbonate and extracted with ethyl acetate (3×8 ml). The combinedorganics were washed with brine and dried over magnesium sulfate.Purification of the concentrate by preparative TLC on silica gel (ethylacetate:hexane (1:1)+1% methanol) gave the title compounds (34 mg4"-ether; 24 mg 3"-ether).

A. (4"-ether)

MASS: (FAB) 831 (M+Na)

Partial ¹ H NMR δ: 5.32 (brs, 1H); 4.87 (brs, 1H); 4.59 (brs, 1H); 4.41(brd J=14 Hz, 1H); 4.19M (brs, 1H); 2.60 (brs, 1H); 1.74 (s, 3H).

B. (3"-ether)

MASS: (FAB) 831 (M+Na)

Partial ¹ H NMR δ: 5.32 (brs, 1H); 4.87 (brs, 1H); 4.81m, 4.23M (brs,1H); 2.63 (brs, 1H); 1.74 (s, 3H).

EXAMPLE 52

17-Ethyl-1,14-dihydroxy-12-2'-(3"-cinnamyloxy-4"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

To a solution of 17-ethyl-1,14-dihydroxy-12-2'-(3",4"-dihydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (100 mg in 3 ml 33%methylene chloride in cyclohexane), cinnamyl trichloroacetimidate (52 μlneat) was added and the reagents allowed to mix for 5 minutes.Trifluoromethanesulfonic acid (2 μl neat) was added slowly via syringeand the mixture stirred at room temperature. After 15 minutes thereaction was quenched by the addition of saturated sodium bicarbonateand extracted with ethyl acetate (3×8 ml). The combined organics werewashed with brine and dried over magnesium sulfate. Purification of theconcentrate by preparative TLC on silica gel (ethyl acetate:hexane(1:1)+1% methanol) gave the title compound (17 mg).

MASS: (FAB) 893 (M+Na)

Partial ¹ H NMR δ: 6.61 (d J=15 Hz, 1H); 6.28 (dt J=15, 6.0 Hz, 1H);5.32m, 5.19M (brd J=3.0 Hz, 1H); 4.82m, 4.22M (brs,1H); 4.52 (brd J=4.0Hz, 1H); 4.41 (brd J=14 Hz, 1H); 2.66 (brs, 1H).

EXAMPLE 53

17-Ethyl-1-hydroxy-12-2'-(4"-hydroxy-3"-isopropoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !-octacos-18-ene-2,3,10,16-tetraone

To a solution of 17-ethyl-1-hydroxy-12-2'-(3",4"-dihydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0.sup.4,9 !octacos-18-ene-2,3,10,16-tetraone (69 mg in 3 ml 33%methylene chloride in cyclohexane), isopropyl trichloroacetimidate (22μl neat) was added and the reagents allowed to mix for 5 minutes.Trifluoromethanesulfonic acid (2 μl neat) was added slowly via syringeand the mixture stirred at room temperature. After 24 hours the reactionwas quenched by the addition of saturated sodium bicarbonate andextracted with ethyl acetate (3×8 ml). The combined organics were washedwith brine and dried over magnesium sulfate. Purification of theconcentrate by preparative TLC on silica gel (ethyl acetate:hexane(1:1)+1% methanol) gave the title compound (12 mg).

MASS: (FAB) 803 (M+Li)

Partial ¹ H NMR δ: 4.87 (brd J=10 Hz, 1H); 4.56 (d J=4.0 Hz, 1H); 4.42m,4.33M (brs, 1H); 2.61 (brs, 1H); 1.16 (d J=7.0 Hz, 6H).

EXAMPLE 54

A. 17-Ethyl-1,14-dihydroxy-12-2'-(4"-sec-butenyloxy-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone and

B. 7-Ethyl-1,14-dihydroxy-12-2'-(3"-sec-butenyloxy-4"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

To a solution of 17-ethyl-1,14-dihydroxy-12-2'-(3",4"-dihydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone(150 mg in 3 ml 33%methylene chloride in cyclohexane), sec-butenyl trichloroacetimidate (62ml neat) was added and the reagents allowed to mix for 5 minutes.Trifluoromethanesulfonic acid (2 μl neat) was added slowly via syringeand the mixture stirred at room temperature. After 15 minutes thereaction was quenched by the addition of saturated sodium bicarbonateand extracted with ethyl acetate (3×8 ml). The combined organics werewashed with brine and dried over magnesium sulfate. Purification of theconcentrate by preparative TLC on silica gel (ethyl acetate:hexane(1:1)+1% methanol) gave the title compounds (11 mg 4"-ether; 13 mg3"-ether).

A. (4"-ether)

MASS: (FAB) 831 (M+Na)

Partial ¹ H NMR δ: 5.65 (m, 1H); 5.32 (brd J=3.0 Hz, 1H); 4.87m, 4.18M(brs, 1H); 4.58 (brd J=4.0 Hz, 1H); 4.41 (brd J=14 Hz, 1H).

B. (3"-ether)

MASS: (FAB) 831 (M+Na)

Partial ¹ H NMR δ: 5.65 (m, 1H); 5.31 (brs, 1H); 4.82m, 4.22M (brs, 1H);4.58 (brd J=4.0 Hz, 1H); 4.41 (brd J=14 Hz, 1H).

EXAMPLE 55

17-Ethyl-1-hydroxy-12-2'-(4"-cinnamyloxy-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricycio22.3.1.0⁴,9 !-octacos-18-ene-2,3,10,16-tetraone

To a solution of 17-ethyl-1-hydroxy-12-2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (100 mg in 3 ml 33%methylene chloride in cyclohexane), cinnamyl trichloroacetimidate (54 μlneat) was added and the reagents allowed to mix for 5 minutes.Trifluoromethanesulfonic acid (2 μl neat) was added slowly via syringeand the mixture stirred at room temperature. After 30 minutes thereaction was quenched by the addition of saturated sodium bicarbonateand extracted with ethyl acetate (3×8 ml). The combined organics werewashed with brine and dried over magnesium sulfate. Purification of theconcentrate by preparative TLC on silica gel (ethyl acetate:hexane(1:2)+1% methanol) gave the title compound (45 mg).

MASS: (FAB) 891 (M+Li)

Partial ¹ H NMR δ: 6.62 (d J=15 Hz, 1H); 6.31 (dt J=15, 6.0 Hz, 1H);4.56 (brd J=4.0 Hz, 1H); 4.31 (d J=6.0 Hz, 2H).

EXAMPLE 56

17-Ethyl-1-hydroxy-12-2'-(3"-methoxy-4"-phenylpropyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9!octacos-18-ene-2,3,10,16-tetraone

To a solution of 17-ethyl-1-hydroxy-12-2'-(4"-cinnamyloxy-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (16 mg in 2 ml ethanol)was added 2 mg of 5% rhodium on carbon catalyst. The reaction flask wasfitted with a hydrogen balloon, evacuated and recharged with hydrogen (3times) and stirred at room temperature. After 30 minutes, the mixturewas filtered over diatomacous earth, concentrated and purified bypreparative TLC on silica gel (ethyl acetate:hexane (1:2)+1% methanol)to give the title compound (5.5 mg).

MASS: (FAB) 916 (M+Na)

Partial ¹ H NMR δ: 4.58 (brd J=4.0 Hz, 1H); 4.42m, 4.32M (brs, 1H); 4.40(brd J=14 Hz, 1H); 2.69 (t J=8.0 Hz, 2H).

EXAMPLE 57

17-Ethyl-1,14-dihydroxy-12-2'-(4"-sec-phenethyloxy-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricycio22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

To a solution of 17-ethyl-1,14-dihydroxy-12-2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (75 mg in 3 ml 33%methylene chloride in cyclohexane), sec-phenethyl trichloroacetimidate(38 μl neat) was added and the reagents allowed to mix for 5 minutes.Trifluoromethanesulfonic acid (3 μl neat) was added slowly via syringeand the mixture stirred at room temperature. After 30 minutes thereaction was quenched by the addition of saturated sodium bicarbonateand extracted with ethyl acetate (3×10 ml). The combined organics werewashed with brine and dried over magnesium sulfate. Purification of theconcentrate by flash chromatography on silica gel (ethyl acetate:hexane(1:2)+1% methanol) gave the title compound (13 mg).

MASS: (FAB) 918 (M+Na) 902 (M+Li)

Partial ¹ H NMR δ: 5.28 (m, 1H); 4.56 (m, 1H); 4.41 (brd J=14 Hz, 1H);4.86m, 4.20M (brs, 1H).

EXAMPLE 58

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-methylcinnamyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

To a solution of 17-ethyl-1,14-dihydroxy-12-2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (50 mg in 1.5 ml 33%methylene chloride in cyclohexane), 2-methylcinnamyltrichloroacetimidate (28 μl neat) was added and the reagents allowed tomix for 5 minutes. Trifluoromethanesulfonic acid (3 μl neat) was addedslowly via syringe and the mixture stirred at room temperature. After 20minutes the reaction was quenched by the addition of saturated sodiumbicarbonate and extracted with ethyl acetate (3×10 ml). The combinedorganics were washed with brine and dried over magnesium sulfate.Purification of the concentrate by flash chromatography on silica gel(ethyl acetate:hexane (1:2)+1% methanol) gave the title compound (9 mg).

MASS: (FAB) 944 (M+Na)

Partial ¹ H NMR δ: 6.53 (brs, 1H); 5.32 (brd, J=3 Hz, 1H); 4.85m, 4.21M(brs, 1H); 4.59 (brd J=4 Hz, 1H); 4.41 (brd J=14 Hz, 1H); 4.16 (brs,2H); 1.90 (brs, 3H).

EXAMPLE 59

17-Ethyl-1,14-dihydroxy-12- 2'-(4"-(4'"-methyl-2'",4'"-hexadienyl-oxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

To a solution of 17-ethyl-1,14-dihydroxy-12-2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (200 mg in 6 ml 33%methylene chloride in cyclohexane), 4-methyl-2,4-hexadienyltrichloroacetimidate (97 μl neat) was added and the reagents allowed tomix for 5 minutes. Trifluoromethanesulfonic acid (5 μl neat) was addedslowly via syringe and the mixture stirred at room temperature. After 4hours the reaction was quenched by the addition of saturated sodiumbicarbonate and extracted with ethyl acetate (3×20 ml). The combinedorganics were washed with brine and dried over magnesium sulfate.Purification of the concentrate by flash chromatography on silica gel(ethyl acetate:hexane (1:2)+1% methanol) gave the title compound (8 mg).

MASS: (FAB) 892 (M+Li)

Partial ¹ H NMR δ: 6.25 (d J=15 Hz, 1H); 5.64 (dt J=15,7 Hz, 1H); 5.31(brd J=3 Hz, 1H); 4.83m, 4.21M (brs, 1H); 4.59 (brd J=4 Hz, 1H); 4.41(brd J=14 Hz, 1H); 4.18 (brd J=7 Hz, 2H).

EXAMPLE 60

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(p-methoxycinnamyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

To a solution of 17-ethyl-1,14-dihydroxy-12-2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (200 mg in 6 ml 33%methylene chloride in cyclohexane), p-methoxycinnamyltrichloroacetimidate (117 μl neat) was added and the reagents allowed tomix for 5 minutes. Trifluoromethanesulfonic acid (3 μl neat) was addedslowly via syringe and the mixture stirred at room temperature. After 20minutes the reaction was quenched by the addition of saturated sodiumbicarbonate and extracted with ethyl acetate (3×20 ml). The combinedorganics were washed with brine and dried over magnesium sulfate.Purification of the concentrate by flash chromatography on silica gel(ethyl acetate:hexane (1:2)+1% methanol) gave the title compound (16mg).

MASS: (FAB) 960 (M+Na) 944 (M+Li)

Partial ¹ H NMR δ: 7.29 (brd J=9 Hz, 2H); 6.85 (brd J=9 Hz, 2H); 5.32M,5.19m (brd J=3 Hz, 1H); 4.84m, 4.21M (brs, 1H); 4.61 (brd J=5 Hz, 2H);4.41 (brd J=14 Hz, 1H).

EXAMPLE 61

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(3'",4'"-methylenedioxycinnamyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

To a solution of 17-ethyl-1,14-dihydroxy-12-2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (200 mg in 6 ml 33%methylene chloride in cyclohexane), 3',4'-methylenedioxycinnamyltrichloroacetimidate (122 μl neat) was added and the reagents allowed tomix for 5 minutes. Trifluoromethanesulfonic acid (3 μl neat) was addedslowly via syringe and the mixture stirred at room temperature. After 30minutes the reaction was quenched by the addition of saturated sodiumbicarbonate and extracted with ethyl acetate (3×20 ml). The combinedorganics were washed with brine and dried over magnesium sulfate.Purification of the concentrate by flash chromatography on silica gel(ethyl acetate:hexane (1:2)+1% methanol) gave the title compound (10mg).

MASS: (FAB) 974 (M+Na)

Partial ¹ H NMR δ: 6.54 (d J=16 Hz, 1H); 6.14 (dt J=16,6 Hz, 1H); 5.95(s, 2H) 5.33M, 5.19m (brd J=3 Hz, 1H); 4.59 (brd J=4 Hz, 1H); 4.41 (brdJ=14 Hz, 1H); 4.27 (brd J=6 Hz, 2H).

EXAMPLE 62

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(4'",4'"-dimethyl-2'"-transpentenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

To a solution of 17-ethyl-1,14-dihydroxy-12-2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (200 mg in 6 ml 33%methylene chloride in cyclohexane), 4,4-dimethyl-2-trans-pentenyltrichloroacetimidate (98 μl neat) was added and the reagents allowed tomix for 5 minutes. Trifluoromethanesulfonic acid (10 μl neat) was addedslowly via syringe and the mixture stirred at room temperature. After1.5 hours the reaction was quenched by the addition of saturated sodiumbicarbonate and extracted with ethyl acetate (3×20 ml). The combinedorganics were washed with brine and dried over magnesium sulfate.Purification of the concentrate by flash chromatography on silica gel(ethyl acetate:hexane (1:2)+1% methanol) gave the title compound (17mg).

MASS: (FAB) 894 (M+Li)

Partial ¹ H NMR δ: 5.70 (d J=16 Hz, 1H); 5.48 (dt J=16,7 Hz, 1H); 5.31(brd J=3 Hz, 1H); 4.84m, 4.21M) (brs, 1H); 4.59 (brd J=4 Hz, 1H); 4.41(brd J=14 Hz, 1H); 4.18 (brd J=7 Hz, 2H); 1.01 (s, 9H).

EXAMPLE 63

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(3'"-cyclohexyl-2'"-transpropenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

To a solution of 17-ethyl-1,14-dihydroxy-12-2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (200 mg in 6 ml 33%methylene chloride in cyclohexane), 3-cyclohexyl-2-trans-propenyltrichloroacetimidate (108 μl neat) was added and the reagents allowed tomix for 5 minutes. Trifluoromethanesulfonic acid (7 μl neat) was addedslowly via syringe and the mixture stirred at room temperature. After 1hour the reaction was quenched by the addition of saturated sodiumbicarbonate and extracted with ethyl acetate (3×20 ml). The combinedorganics were washed with brine and dried over magnesium sulfate.Purification of the concentrate by flash chromatography on silica gel(ethyl acetate:hexane (1:2)+1% methanol) gave the title compound (20mg).

MASS: (FAB) 936 (M+Na)

Partial ¹ H NMR δ: 5.32M, 5.19m (brd J=3 Hz, 1H); 4.84m, 4.21M (brs,1H); 4.59 (brd J=4 Hz, 1H); 4.41 (brd J=14 Hz, 1H); 4.06 (brd J=5 Hz,2H).

EXAMPLE 64

17-Ethyl-1,14-dihydroxy-12-2'-(4"-p-fluorocinnamyloxy-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

To a solution of 17-ethyl-1,14-dihydroxy-12-2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (200 mg in 6 ml 33%methylene chloride in cyclohexane), p-fluorocinnamyltrichloroacetimidate (112 μl neat) was added and the reagents allowed tomix for 5 minutes. Trifluoromethanesulfonic acid (7 μl neat) was addedslowly via syringe and the mixture stirred at room temperature. After 20minutes the reaction was quenched by the addition of saturated sodiumbicarbonate and extracted with ethyl acetate (3×20 ml). The combinedorganics were washed with brine and dried over magnesium sulfate.Purification of the concentrate by flash chromatography on silica gel(ethyl acetate:hexane (1:2)+1% methanol) gave the title compound (33mg).

MASS: (FAB) 932 (M+Li)

Partial ¹ H NMR δ: 7.37 (d J=6 Hz, 1H); 7.31 (d J =6 Hz, 1H); 7.01 (dJ=9 Hz, 1H); 6.96 (d J=9 Hz, 1H); 6.57 (d J=16 Hz, 1H); 6.21 (dt J=16, 6Hz, 1H); 5.32M, 5.19m (brd J=3 Hz, 1H); 4.83m, 4.21M (brs, 1H); 4.59(brd J=4 Hz, 1H); 4.41 (brd J=14 Hz, 1H); 4.29 (d J=6 Hz, 2H).

EXAMPLE 65

17-Ethyl-1,14-dihydroxy-12-2'-(4"-p-chlorocinnamyloxy-3"-methoxy-cyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

To a solution of 17-ethyl-1,14-dihydroxy-12-2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (200 mg in 6 ml 33%methylene chloride in cyclohexane), p-chlorocinnamyltrichloroacetimidate (119 μl neat) was added and the reagents allowed tomix for 5 minutes. Trifluoromethanesulfonic acid (7 μl neat) was addedslowly via syringe and the mixture stirred at room temperature. After 30minutes the reaction was quenched by the addition of saturated sodiumbicarbonate and extracted with ethyl acetate (3×20 ml). The combinedorganics were washed with brine and dried over magnesium sulfate.Purification of the concentrate by flash chromatography on silica gel(ethyl acetate:hexane (1:2)+1% methanol) gave the title compound (34mg).

MASS: (FAB) 948 (M+Li)

Partial ¹ H NMR δ: 6.58 (d J=16 Hz, 1H); 6.27 (dt J=16, 6 Hz, 1H);5.32M, 5.19m (brd J=3 Hz, 1H); 4.84m, 4.21M (brs, 1H); 4.59 (brd J=4 Hz,1H); 4.41 (brd J=14 Hz, 1H); 4.30 (d J=6 Hz, 1H).

EXAMPLE 66

17-Ethyl-1,14-dihydroxy-12-2'-(4"-p-bromocinnamyloxy-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricycio22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

To a solution of 17-ethyl-1,14-dihydroxy-12-2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (200 mg in 6 ml 33%methylene chloride in cyclohexane), p-bromocinnamyl trichloroacetimidate(135 μl neat) was added and the reagents allowed to mix for 5 minutes.Trifluoromethanesulfonic acid (7 μl neat) was added slowly via syringeand the mixture stirred at room temperature. After 1 hour the reactionwas quenched by the addition of saturated sodium bicarbonate andextracted with ethyl acetate (3×20 ml). The combined organics werewashed with brine and dried over magnesium sulfate. Purification of theconcentrate by flash chromatography on silica gel (ethyl acetate:hexane(1:2)+1% methanol) gave the title compound (19 mg).

MASS: (FAB) 984,986 (M+)

Partial ¹ H NMR δ: 7.42 (d J=9 Hz, 2H); 7.20 (d J=9 Hz, 2H); 6.56 (dJ=16 Hz, 1H); 6.29 (dt J=16, 6 Hz, 1H); 5.31M, 5.19m (brd J=3 Hz, 1H);4.85m, 4.21M(brs, 1H); 4.59 (brd J=4 Hz, 1H); 4.41 (brd J=14 Hz, 1H);4.28 (d J=6 Hz, 2H).

EXAMPLE 67

17-Ethyl-1,14-dihydroxy-12-2'-(3"-methoxy-4"-p-fluorophenpropyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

To a solution of 17-ethyl-1,14-dihydroxy-12-2'-(4"-p-fluorocinnamyloxy-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (22 mg in 2 ml ethanol)was added 6 mg of 5% rhodium on carbon catalyst. The reaction flask wasfitted with a hydrogen balloon, evacuated and recharged with hydrogen (3times) and stirred at room temperature. After 45 minutes, the mixturewas filtered over Celite, concentrated and purified by preparative TLCon silica gel (ethyl acetate:hexane (1:2)+1% methanol) to give the titlecompound (7.5 mg).

MASS: (FAB) 934 (M+Li)

Partial ¹ H NMR δ: 7.16 (d J=6 Hz, 1H); 7.12 (d J=6 Hz, 1H); 6.97 (d J=9Hz, 1H); 6.92 (d J=9 Hz, 1H); 5.32M, 5.19m (brd J=3 Hz, 1H); 4.85m,4.21M (brs, 1H); 4.59 (brd J=4 Hz, 1H); 4.41 (brd J=14 Hz, 1H); 2.67 (tJ=8 Hz, 2H).

EXAMPLE 68

17-Ethyl-1-hydroxy-12-2'-(3",4"-diallyloxy-cyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0.sup.4,9 !octacos-18-ene-2,3,10,16-tetraone

To a solution of 17-ethyl-1-hydroxy-12-2'-(3",4"-dihydroxycyclohexyl)-1'-methhylvinyl!-23,25-dimethoxyo13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo 22.3.1.0⁴,9!octacos-18-ene-2,3,10,16-tetraone (20 mg in 0.75 ml 33% methylenechloride in cyclohexane), allyl trichloroacetimidate (16 μL neat) wasadded and the reagents allowed to mix for 5 minutes.Trifluoromethanesulfonic acid (2.0 μL neat) was added slowly via syringeand the mixture stirred at room temperature. After 5 hours the reactionwas quenched by the addition of saturated sodium bicarbonate andextracted with ethyl acetate (3×5 ml). The combined organics were washedwith brine and dried over magnesium sulfate. Purification of theconcentrate by flash chromatography on silica gel (ethyl acetate:hexane(1:3)+1% methanol) gave the title compound (6.8 mg). (¹ H NMR wasconsistent with the desired structure).

EXAMPLE 69

17-Ethyl-1-hydroxy-12-2'-(3",4"-dipropyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0.sup.4,9 !octacos-18-ene-2,3,10,16-tetraone

To a solution of 17-ethyl-1-hydroxy-12-2'-(3",4"-diallyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0.sup.4,9 !octacos-18-ene-2,3,10,16-tetraone (6.8 mg in 600 μlethyl acetate) was added 4 mg of 5% rhodium on carbon catalyst. Thereaction flask was fitted with a hydrogen balloon, evacuated andrecharged with hydrogen (3 times) and stirred at room temperature. After25 minutes, the mixture was filtered over Celite, concentrated andpurified by flash chromatography on silica gel (ethyl acetate:hexane(1:3)+1% methanol) to give the title compound (4.5 mg).

MASS: (FAB) 852 (M+Li)

Partial ¹ H NMR δ: 4.59 (brm, 1H); 4.42m, 4.33M (brs, 1H); 4.41 (brd,J=14 Hz, 1H); 3.54 (m, 4H).

EXAMPLE 70

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-benzylamino)-ethoxy-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

Step A: 17-Ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-2'-(4"-(tert-butyldimethylsiloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

To a solution of 17-ethyl-1,14-dihydroxy-12-2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (2.35 g) in dry methylenechloride (20 ml) was added an excess of 2,6-lutidine (1.04 ml) and themixture was stirred at room temperature. After 10 minutes,tert-butyldimethylsilyl trifluoromethanesulfonate (1.50 ml) was addedvia syringe. After 1 hour the reaction mixture was diluted with ethylacetate, extracted from saturated sodium bicarbonate, washed with brineand the organic phase dried over magnesium sulfate. Removal of thesolvent in vacuo and flash chromatography on silica gel (ethylacetate:hexane (1:3)+1% methanol) gave the title compound (2.91 g). (¹ HNMR was consistent with the desired structure).

Step B: 17-Ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

To a solution of 17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-2'-(4"-(tert-butyldimethylsiloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacoso-18-ene-2,3,10,16-tetraone (2.91 g) in acetonitrile(15 ml) was added a solution of 2% hydrogen fluoride in aqueousacetonitrile (2 ml), and the mixture stirred at room temperature. After4 hours, the solution was diluted with ethyl acetate, extracted withsaturated sodium bicarbonate solution and the organic phase dried overmagnesium sulfate. Purification of the concentrate by flashchromatography on silica gel (ethyl acetate:hexane (1:1)+1% methanol)gave the title compound (1.51 g). (¹ H NMR was consistent with thedesired structure).

Step C: 17-Ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-2'-(4"-allyloxy-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

To a solution of 17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (820 mg in 9 ml 33%methylene chloride in cyclohexane) allyl trichloroacetimidate (366 μlneat) was added and the reagents allowed to mix for 5 minutes.Trifluoromethanesulfonic acid (16 μl neat) was added slowly via syringeand the mixture stirred at room temperature. After 17 hours the reactionwas quenched by the addition of saturated sodium bicarbonate andextracted with ethyl acetate (3×15 ml). The combined organics werewashed with brine and dried over magnesium sulfate. Purification of theconcentrate by flash chromatography on silica gel (ether:hexane (2:3))gave the title compound (800 mg). (¹ H NMR was consistent with thedesired structure).

Step D: 17-Ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-2'-(4"-(2'",3'"-dihydroxypropyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

To a solution of 17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-2'-(4"-allyloxy-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (344 mg in 3 ml drydiethyl ether) was added 150 μl pyridine followed by 1.6 ml of a 0.25Mosmium tetraoxide solution in THF and the mixture stirred at roomtemperature. After 15 minutes, 10 ml of a 20% sodium bisulfite solutionwere added and the mixture diluted with 20 ml ethyl acetate. The layerswere separated and the organic portion re-extracted with 20% sodiumbisulfite (3×20 ml) then washed with a saturated brine solution anddried over sodium sulfate. The concentrate was purified by flashchromatography on silica gel (ethyl acetate:hexane (1:1)+1% methanol,then methylene chloride:hexane:methanol (10:2:1)) to give the titlecompound (300 mg) (¹ H NMR was consistent with the desired structure).

Step E: 17-Ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-2'-(4"-ethanaloxy-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azaricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

To a solution of 17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-2'-(4"-(2'",3'"-dihydroxypropyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (284 mg in 6 ml of in 20%aqueous tetrahydrofuran) was added sodium metaperiodate (72.3 mg) andthe mixture stirred vigorously for 2 hours. At this time an additional50 mg of sodium metaperiodate were added. After 1.5 hours the mixturewas diluted with ethyl acetate and extracted from half-saturated sodiumbicarbonate. The organic portion was dried over magnesium sulfate andpurified by flash chromatography on silica gel (ethyl acetate:hexane(1:1)+1% methanol) to give the title compound (151 mg). (¹ H NMR wasconsistent with the desired structure).

Step F: 17-Ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-2'-(4"-(2'"-benzylamino)-ethoxy-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

To a solution of 17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-2'-(4"-ethanaloxy-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (9.5 mg in 0.25 ml dryterahydrofuran) was added benzylamine (2.5 μl) and the mixture stirredfor 10 minutes at room temperature. This was cooled to -78° C. andacetic acid (10 μl) was added followed by potassium triphenylborohydride(25 μl of a 0.5M solution in THF). After 45 minutes, the reaction wasquenched by the addition of saturated ammonium chloride and warmed toroom temperature. The mixture was extracted with ethyl acetate (3×5 ml)and dried over magnesium sulfate. The concentrate was purified by flashchromatography on silica gel (ethyl acetate:hexane (1:2)+1% methanol,then 2% ammonium hydroxide, 5% methanol in methylene chloride) to givethe title compound (3.5 mg).

MASS (FAB) 1039 (M+). (¹ H NMR was consistent with the desiredstructure).

Step G: 17-Ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-benzylamino)ethoxy-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

To a solution of 17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-2'-(4"-(2'"-benzylamino)ethoxy-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (3.5 mg) in acetonitrile(100 μl) was added a solution of 2% HF in aqueous acetonitrile (100 μl),and the mixture stirred at room temperature. After 2 hours, the solutionwas diluted with ethyl acetate, extracted with saturated sodiumbicarbonate solution and the organic phase dried over magnesium sulfate.Purification of the concentrate by flash chromatography on silica gel(ethyl acetate:hexane (1:1)+1% methanol, then 2% ammonium hydroxide, 5%methanol in methylene chloride) gave the title compound (2 mg).

MASS (FAB) 925 (M+)

Partial ¹ H NMR δ: 7.32 (m, 5H); 5.32M, 5.17m (brd J=3 Hz, 1H); 4.84m,4.21M (brs, 1H); 4.59 (brd, J=4 Hz, 1H); 4.41 (brd J=14 Hz. 1H); 3.84(brs, 2H).

EXAMPLE 71

17-Ethyl-1-hydroxy-12-2'-(4"-(2'"-benzylamino)ethoxy-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

Step A: 17-Ethyl-1-hydroxy-12-2'-(4"-allyloxy-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

To a solution of 17-ethyl-1-hydroxy-12-2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (400 mg in 6 ml 33%methylene chloride in cyclohexane), allyl trichloroacetimidate (209 μlneat) was added and the reagents allowed to mix for 5 minutes.Trifluoromethanesulfonic acid (9 μl neat) was added slowly via syringeand the mixture stirred at room temperature. After 6 hours the reactionwas quenched by the addition of saturated sodium bicarbonate andextracted with ethyl acetate (3×10 ml). The combined organics werewashed with brine and dried over magnesium sulfate. Purification of theconcentrate by flash chromatography on silica gel (ethyl acetate:hexane(1:3)+1% methanol) gave the title compound (320 mg). (¹ H NMR wasconsistent with the desired structure).

Step B: 17-Ethyl-1-hydroxy-12-2'-(4"-(2'",3'"-dihydroxypropyloxy)-3"-methoxycyclohexyl)-1'-methyl-vinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

To a solution of 17-ethyl-1-hydroxy-12-2'-(4"-allyloxy-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (310 mg in 3.5 ml dryether) was added 350 μl pyridine followed by 1.5 ml of a 0.25M osmiumtetraoxide solution in THF and the mixture stirred at room temperature.After 15 minutes, 10 ml of a 20% sodium bisulfite solution were addedand the mixture diluted with 20 ml ethyl acetate. The layers wereseparated and the organic portion re-extracted with 20% sodium bisulfite(3×20 ml) then washed with a saturated brine solution and dried oversodium sulfate. The concentrate was purified by flash chromatography onsilica gel (ethyl acetate:hexane (1:1)+1% methanol, then methylenechloride:hexane:methanol (10:2:1)) to give the title compound (232 mg).(¹ H NMR was consistent with the desired structure).

Step C: 17-Ethyl-1-hydroxy-12-2'-(4"-ethanaloxy-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

To a solution of 17-ethyl-1-hydroxy-12-2'-(4"-(2'",3'"-dihydroxypropyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (232 mg in 25% aqueoustetrahydrofuran) was added sodium metaperiodate (70.2 mg) and themixture stirred vigorously. After 4 hours the mixture was diluted withethyl acetate and extracted from half-saturated sodium bicarbonate. Theorganic portion was dried over magnesium sulfate and purified by flashchromatography on silica gel (ethyl acetate:hexane (1:1)+1% methanol) togive the title compound (112 mg). (¹ H NMR was consistent with thedesired structure).

Step D: 17-Ethyl-1-hydroxy-12-2'-(4"-(2'"-benzylamino)-ethoxy-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

To a solution of 17-ethyl-1-hydroxy-12-2'-(4"-ethanaloxy-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (4 mg in 0.30 ml dryterahydrofuran) was added benzylamine (2.0 μl) and the mixture stirredfor 10 minutes at room temperature. This was cooled to -78° C. andacetic acid (7 μl) was added followed by potassium triphenylborohydride(16 μl of a 0.5M solution in THF). After 35 minutes, the reaction wasquenched by the addition of saturated ammonium chloride and warmed toroom temperature. The mixture was extracted with ethyl acetate (3×5 ml)and dried over magnesium sulfate. The concentrate was purified by flashchromatography on silica gel (ethyl acetate:hexane (1:2)+1% methanol,then 2% ammonium hydroxide, 5% methanol in methylene chloride) to givethe title compound (2.1 mg).

Partial ¹ H NMR δ: 7.32 (m, 5H); 4.56 (brd, J=4 Hz, 1H); 4.41 (brd J=14Hz, 1H); 3.82 (brs, 2H).

EXAMPLE 72

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-benzyloxyethoxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

Step A: 17-Ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-2'-(4"-(2-hydroxyethoxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

To a solution of 17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-2'-(4"-ethanaloxy-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (126 mg in 1.3 ml dryterahydrofuran) at -78° C. was added potassium triphenylborohydride (320μl of a 0.5M solution in THF). After 45 minutes, the reaction wasquenched by the addition of saturated ammonium chloride and warmed toroom temperature. The mixture was extracted with ethyl acetate (3×15 ml)and dried over magnesium sulfate. The concentrate was purified by flashchromatography on silica gel (ethyl acetate:hexane (2:1+1% methanol) togive the title compound (80.2 mg). (¹ H NMR was consistent with thedesired structure).

Step B: 17-Ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-2'-(4"-(2-benzyloxyethoxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

To a solution of 17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-2'-(4"-(2-hydroxyethoxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23!25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (41.7 mg in 0.6 ml 33%methylene chloride in cyclohexane), benzyl trichloroacetimidate (15.8 μlneat) was added and the reagents allowed to mix for 5 minutes.Trifluoromethanesulfonic acid (2 μl neat) was added slowly via syringeand the mixture stirred at room temperature. After 7 hours the reactionwas quenched by the addition of saturated sodium bicarbonate andextracted with ethyl acetate (3×5 ml). The combined organics were washedwith brine and dried over magnesium sulfate. Purification of theconcentrate by flash chromatography on silica gel (ethyl acetate:hexane(1:3)+1% methanol) gave the title compound (24 mg). (¹ H NMR wasconsistent with the desired structure).

Step C: 17-Ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-benzyloxy-ethoxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

To a solution of 17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-2'-(4"-(2'"-benzyloxyethoxy)-3"-methoxycyclo-hexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone(10 mg) in acetonitrile(500 μl) was added a solution of 2% HF in aqueous acetonitrile (200 μl),and the mixture stirred at room temperature. After 2.5 hours, thesolution was diluted with ethyl acetate, extracted with saturated sodiumbicarbonate solution and the organic phase dried over magnesium sulfate.Purification of the concentrate by flash chromatography on silica gel(ethyl acetate:hexane (1:2)+1% methanol) gave the title compound (4 mg).

MASS (FAB) 932 (M+Li).

Partial ¹ H NMR δ: 7.33(m, 5H); 5.32M, 5.19m (brd J=3 Hz, 1H); 4.85m,4.21M (brs, 1H); 4.58 (s 2H); 4.41 (brd J=14 Hz, 1H).

EXAMPLE 73

17-Ethyl-1,14-dihydroxy-12-2'-(4"-benzyloxymethoxy-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

To a solution of 17-ethyl-1,14-dihydroxy-12-2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (150 mg in 2 ml methylenechloride) was added disopropylethylamine (99.4 μl) followed by benzylchloromethyl ether (34.2 μl neat) and the mixture stirred at roomtemperature. After 24 hours, the reaction was quenched by the additionof saturated sodium bicarbonate and extracted with ethyl acetate (3×20ml). The combined organics were washed with brine and dried overmagnesium sulfate. Purification of the concentrate by flashchromatography on silica gel (ethyl acetate:hexane (1:2)+1% methanol)gave the title compound (92 mg).

MASS: (FAB) 918 (M+Li).

Partial ¹ H NMR δ: 7.33 (m, 5H); 5.32M, 5.19m (brd J=3 Hz, 1H); 4.87 (s,2H); 4.63 (s, 2H); 4.59 (brd J=4 Hz, 1H); 4.41 (brd J=14 Hz, 1H).

EXAMPLE 74

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(napth-2-yloxy)-3"-allyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !ocacos-18-ene-2,3,10,16-tetraone

To a solution of 17-ethyl-1,14-dihydroxy-12-2'-(4"-(napth-2-yloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone in 33% methylenechloride/cyclohexane is added 1.5 equivalents of allyltrichloro-acetimidate, and the reagents are allowed to mix for 5minutes. A catalytic amount of trifluoromethanesulfonic acid is thenadded slowly via syringe and the mixture is stirred at room temperature.After 3 hours the reaction is quenched by the addition of saturatedsodium bicarbonate and extracted with ethyl acetate. The combinedorganics are washed with brine and dried over magnesium sulfate.Purification of the concentrate by flash chromatography on silica gelgives the title compound.

EXAMPLE 75

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(4'"-t-butyldimethylsiloxycinnamyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

To a solution of 17-ethyl-1,14-dihydroxy-12-2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,-10,16-tetraone (700 mg in 12 mlmethylene chloride)4-t-butyldimethylsiloxycinnamyl trichloroacetimidate(550 μl neat) was added and the reagents allowed to mix for 5 minutes.Camphorsulfonic acid (35 mg) was added and the mixture stirred at roomtemperature. After 5 hours the reaction was quenched by the addition ofsaturated sodium bicarbonate and extracted with ethyl acetate (3×15 ml).The combined organics were washed with brine and dried over magnesiumsulfate. Purification of the concentrate by flash chromatography onsilica gel (ethyl acetate:hexane (1:2)+1% methanol) gave the titlecompound (190 mg).

¹ H NMR spectrum was consistent with the desired structure.

EXAMPLE 76

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(4'"-hydroxycinnamyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

To a solution of 17-ethyl-1,14-dihydroxy-12-2'-(4"-(4'"-t-butyldimethylsiloxycinnamyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (190 mg in 2 mltetrahydrofuran contained in a polypropylene vial) was added 500 μl of asolution of hydrogen fluoride-pyridine complex (40% in (2:1)tetrahydrofuran:pyridine) and the mixture stirred at room temperature.After 2 hours, the reaction was quenched by the careful addition ofsaturated sodium bicarbonate and extracted with ethyl acetate. Thecombined organics were dried over magnesium sulfate, concentrated invacuo and purified by flash chromatography on silica gel (ethylacetate:hexane (2:1) to give the title compound (50 mg).

MS(FAB) 930 (M+Li).

¹ H NMR spectrum was consistent with the desired structure.

EXAMPLE 77

17-Ethyl-1,14,dihydroxy-12-2'-(4"-(2'"-phenyl-2'"-oxo-ethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

Step A: 17-Ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-2'-4"-(2'"-phenyl-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'methylivinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

To a solution of 17-ethyl-1-hydroxy-14-(ten-butyldimethylsiloxy)-12-2'-(4"-ethanaloxy-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (41 mg in 0.5 mlmethylene chloride) at -78° C. was added phenylmagnesium bromide (15 μLof a 3M solution in diethyl ether) and the mixture stirred a lowtemperature. After 30 minutes the reaction was quenched by addition ofsaturated ammonium chloride and extracted with ethyl acetate. Theorganics were dried by passage through a magnesium sulfate plug and theconcentrate purified by flash chromatography on silica gel (ethylacetate:hexane (1:2)+1% methanol then (1:1+1% methanol) to give thetitle compound (13 mg).

(¹ H NMR consistent with the desired structure)

Step B: 17-Ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-2'-(4"-(2'"-phenyl-2'"-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

To solution of 17 ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-2'-(4"-(2'"-phenyl-2'"hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (13 mg in 0.3 mLmethylene chloride) was added powdered 4 Å molecular sieves (10 mg),4-methylmorpholine N-oxide (6.0 mg), tetrapropylammonium perruthenate(1.0 mg) and the reaction stirred at room temperature. After 30 minutesthe mixture was filtered through a small diatomaceous earth/silica gelplug and the filtrate concentrated in vacuo. Purification by flashchromatography on silica gel (ethyl acetate:hexane (1:2)+1% methanol)gave the title compound (10 mg).

(¹ H NMR consistent with the desired structure)

Step C: 17-Ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-phenyl-2'"-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

To a solution of 17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-2'-(4"-(2'"-phenyl-2'"-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (10 mg in 0.4 mLtetrahydrofuran contained in a polypropylene vial) was added 20 μL of asolution of hydrogen fluoride-pyridine complex (40% in (2:1)tetrahydrofuran:pyridine) and the mixture stirred at room temperature.After 96 hours, the reaction was quenched by the careful addition ofsaturated sodium bicarbonate and extracted with ethyl acetate. Thecombined organics were dried by passage through a magnesium sulfateplug, concentrated in vacuo and purified by flash chromatography (ethylacetate:hexane (1:1)+1% methanol) to give the title compound (5.2 mg).

MASS: (FAB) 917(M+Li)

Partial ¹ H NMR δ: 7.92 (d J=7 Hz, 2H); 7.47 (m, 3H); 5.31M, 5.17m (brdJ=3 Hz, 1H); 4.81m, 4.20M (brs, 1H); 4.41 (brd J=14 Hz, 1H); 3.06 (d J=4Hz, 1H).

EXAMPLE 77B

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-phenyl-2'"-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

Step A: 17-Ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-2'-(4"-(2'"-phenyl-2'"-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

To a solution of 17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0.⁴,9 !octacos-18-ene-2,3,10,16-tetraone (400 mg in 3.0 mLN,N-dimethylformamide) was added 2-bromoacetophenone (263 mg) followedby potassium fluoride (25.6 mg) and the mixture heated to 70° C. After48 hours, the mixture was cooled to room temperature, filtered overdiatomaceous earth, diluted with ethyl acetate and washed with saturatedsodium bicarbonate, water, and brine. The combined organics were driedover magnesium sulfate and concentrated in vacuo. Purification by flashchromatography on silica gel (ethyl acetate:hexane (1:2)+1% methanol)gave the desired product (145 mg).

(¹ H NMR consistent with the desired structure).

Step B: 17-Ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-phenyl-2'"-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

Conducted essentially as described in Example 77 Step C to give thedesired product (86 mg).

(¹ H NMR consistent with the desired structure).

EXAMPLE 78

17-Ethyl-1,14-dihydroxy-12-2'-(4"-2'"-(3""-methyoxyphenyl)-2'"-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19-21,27-tetramethyl-11,28-dioxa-4-azatricyclo-22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

The title compound was prepared employing the procedure essentially asdescribed in Example 77, Steps A-C using 3-methoxyphenylmagnesiurnbromide as the nucleophile in Step A.

MASS: (FAB) 940(M+)

Partial ¹ H NMR δ: 7.46 (m, 2H); 7.33 (t J=8 Hz, 1H); 7.09 (dd J=8,2 Hz,1H); 5.31M, 5.17m (brd J=3 Hz, 1H); 4.81m, 4.20M (brs, 1H); 4.41 (brdJ=14 Hz, 1H); 3.84 (s, 3H); 3.07 (d J=Hz, 1H).

EXAMPLE 79

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3""-methoxyphenyl)-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricylo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

To a solution of 17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-2'-(4"-(2'"-(3""-methyoxyphenyl)-2'"-hydroxyethyloxy-)3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0.sup.4,9 !octacos-1-8-ene-2,3,10,16-tetrone (29 mg in 0.6 mLtetrahydrofuran contained in a polypropylene vial) was added 80 μL of asolution of hydrogen fluoride-pyridine complex (40% in (2:1)tetrahydrofuran:pyridine) and the mixture stirred at room temperature.After 48 hours, the reaction was quenched by the careful addition ofsaturated sodium bicarbonate and extracted with ethyl acetate. Thecombined organics were dried by passage through a magnesium sulfateplug, concentrated in vacuo and purified by flash chromatography (ethylacetate:hexane (1:1)+1% methanol) to give the title compound (9.5 mg).

MASS (FAB) 942 (M+)

Partial ¹ H NMR δ: 7.23 (m, 1H); 6.94 (s, 1H); 6.91 (d J=8 Hz, 1H); 6.79(d J=8 Hz, 1H); 5.31M, 5.17m (brd J=3 Hz, 1H); 4.41 (brd J=14 Hz, 1H);3.78 (s, 3H); 3.07 (d J=4 Hz, 1H).

EXAMPLE 80

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(4""-methoxyphenyl)-2'"-oxo-ethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricylo22.3.1.0⁴,9 !octacos-18-ene-23,10,16-tetraone

The title compound was prepared employing the procedure essentially asdescribed in Example 77, Steps A-C using 4-methoxyphenylmagnesiumbromide as the nucelophile in Step A.

MASS (FAB) 940 (M+)

Partial ¹ H NMR δ: 7.92 (d J=9 Hz,2H); 6.91 (d J=9 Hz, 2H); 1H); 5.31M,5.17m (brd J=3 Hz, 1H); 4,81m, 4.20M (brs, 1H); 4.41 (brd J=14 Hz, 1H);3.84 (s, 3H); 3.07 (d J=4 Hz, 1H).

EXAMPLE 81

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(m-fluorocinnamyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

Prepared essentially as described in Example 44 using m-fluorocinnamyltrichloroacetimidate as the electrophile.

MASS (FAB) 948 (M+Na)

Partial ¹ H NMR δ: 7.30-6.85 (m, 4H); 6.59 (d J=17 Hz, 1H); 6.30 (dtJ=17, 6 Hz, 1H); 5.30M, 5.17m (brd J=3 Hz, 1H); 4.41 (d J=14 Hz, 1H);4.31 (d J=5 Hz, 2H).

EXAMPLE 82

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(3'",5'"-difluorocinnamyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

Prepared essentially as described in Example 44 using3,5-difluorocinnamyl trichloroacetimidate as the electrophile.

MASS (FAB) 950 (M+Li)

Partial ¹ H NMR δ: 6.92-6.56 (m, 3H); 6.55 (d J=16 Hz, 1H); 6.31 (dtJ=16, 6 Hz, 1H); 5.30M, 5.17m (brd J=3 Hz, 1H); 4.41 (d J=14 Hz, 1H);4.31 (d J=5 Hz, 2H).

EXAMPLE 83

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(m-nitrocinnamyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

Step A: 17-Ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-2'-(4"-(m-nitrocinnamyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

Prepared essentially as described in Example 70 (Step C) usingm-nitrocinnamyl trichloroacetimidate as the electrophile.

¹ H NMR consistent with the desired structure.

Step B: 17-Ethyl-1,14-dihydroxy-12-2'-(4"-(m-nitrocinnamyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

To a solution of 17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-2'-(4"-(m-nitrocinnamyloxy)-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (124 mg in 1.5 mLtetrahydrofuran contained in a polypropylene vial) was added 600 mL of asolution of hydrogen fluoride-pyridine complex (40% in (2:1)tetrahydrofuran:pyridine) and the mixture stirred at room temperature.After 30 hours, the reaction was quenched by the careful addition ofsaturated sodium bicarbonate and extracted with ethyl acetate. Thecombined organics were dried by passage through a magnesium sulfateplug, concentrated in vacuo and purified by flash chromatography onsilica gel (ethyl acetate:hexane (1:1) 1% methanol) to give the titlecompound (43 mg).

MASS (FAB) 959 (M+Li)

Partial ¹ H NMR δ: 8.22 (s, 1H); 8.06 (brd J=8 Hz, 1H); 7.66 (brd J=8Hz, 1H); 7.46 (t J=8 Hz, 1H); 6.69 (d J=16 Hz, 1H); 6.44 (dt J=16, 6 Hz,1H); 5.30M, 5.17m (brd J=3 Hz, 1H); 4.41 (d J=14 Hz, 1H).

EXAMPLE 84

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(3'"-phenyl-2-propynyloxy)-3"-methoxycylohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

Prepared essentially as described in Example 83 using 3-phenylpropynyltrichloroacetimidate as the electrophile.

MASS (FAB) 912 (M+Li)

Partial ¹ H NMR δ: 7.54-7.28 (m, 5H); 5.30M, 5.17m (brd J=3 Hz, 1H);4.41 (d J=14 Hz, 1H).

EXAMPLE 85

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-phenyl-2'"-propenyloxy)-3"-methoxycylohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

Prepared essentially as described in Example 83 using2-phenyl-2-propenyl trichloroacetimidate as the electrophile.

MASS (FAB) 915 (M+Li)

Partial ¹ H NMR δ: 7.47 (d J=8 Hz, 2H); 7.26 (m, 3H); 5.49 (s, 1H); 5.37(s, 1H); 5.30M, 5.17m (brd J=3 Hz, 1H); 4.41 (d J=14 Hz, 1H).

EXAMPLE 86

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(p-hydroxycinnamyloxy)-3"-methoxycylohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

Prepared essentially as described in Example 83 usingp-(tert-butyldimethylsiloxy)cinnamyl trichloroacetimidate as theelectrophile.

MASS (FAB) 930 (M+Li)

Partial ¹ H NMR δ: 7.22 (d J=10 Hz, 2H); 6.76 (d J=10 Hz, 2H); 6.51 (dJ=16 Hz, 1H); 6.11 (dt J=16, 6 Hz, 1H); 5.30M, 5.17m (brd J=3 Hz, 1H);4.41 (d J=14 Hz, 1H).

EXAMPLE 87

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(p-hydroxyphenpropyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

Prepared essentially as described in Examples 83(Step A), 56, 83(Step B)using p-(tert-butyldimethylsiloxy)cinnamyl trichloroacetimidate as theelectrophile.

MASS (FAB) 949 (M+Na)

Partial ¹ H NMR δ: 7.04 (d J=9 Hz, 2H); 6.72 (d J=9 Hz, 2H); 5.30M,5.17m (brd J=3 Hz, 1H); 4.41 (d J=14 Hz, 1H).

EXAMPLE 88

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(m-hydroxycinnamyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

Prepared essentially as described in Example 83 usingm-(tert-butyldimethylsiloxy)cinnamyl trichloroacetimidate as theelectrophile.

MASS (FAB) 930 (M+Li)

Partial ¹ H NMR δ: 7.17-6.63 (m, 5H); 6.52 (d J=16 Hz, 1H); 6.23 (dtJ=16, 6 Hz, 1H); 5.69 (s, 1H); 5.30M, 5.17m (brd J=3 Hz, 1H); 4.41 (dJ=14 Hz, 1H).

EXAMPLE 89

17-Ethyl-1,14-dihydroxy-12- 2'-(4"-(m-hydroxymethylbenzyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

Step A: 17-Ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-2'-(4"-(m-hydroxymethylbenzyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !-octacos-18-ene-2,3,10,16-tetraone

Prepared essentially as described in Example 70 (Step C) usingm-(tert-butyldimethylsiloxymethyl)-benzyl trichloroacetimidate as theelectrophile.

¹ H NMR consistent with the desired structure.

Step B: 17-Ethyl-1,14-dihydroxy-12-2'-(4"-(m-hydroxymethyl)benzyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

To a solution of 17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-2'-(4"-(m-tert-butyldimethylsiloxymethyl)-benzyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (19.7 mg) in acetonitrile(0.5 ml) was added a solution of 2% HF in aqueous acetonitrile (40 ml),and the mixture stirred at room temperature. After 3.5 hours, thesolution was diluted with ethyl acetate, extracted with saturated sodiumbicarbonate solution and the organic phase dried over magnesium sulfate.Purification of the concentrate by flash chromatography on silica gel(ethyl acetate:hexane (1:1)+1% methanol) gave the title compound (6 mg).

MASS (FAB) 934 (M+Na)

Partial ¹ H NMR δ: 7.41-7.22 (m, 4H); 5.30M, 5.17m (brd J=3 Hz, 1H);4.41(d J=14 Hz, 1H).

EXAMPLE 90

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(m-hydroxycinnamyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

Step A: 17-Ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-2'-(3",4"-di(tert-butyldimethylsiloxy)-cyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

To a solution of 17-ethyl-1,14-dihydroxy-12-2'-(3",4"-dihydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (8.0 g) in dry methylenechloride (150 mL) was added an excess of 2,6-lutidine (4.8 mL) and themixture was stirred at room temperature. After 10 minutes,tert-butyldimethylsilyl trifluoromethanesulfonate (7.57 mL) was addedvia syringe. After 1 hour the reaction mixture was diluted with ethylacetate, extracted from 1N hydrochloric acid, washed with water,saturated sodium bicarbonate, brine, and the organic phase dried overmagnesium sulfate. Removal of the solvent in vacuo gave the titlecompound (crude 12.5 g).

¹ H NMR consistent with the desired structure.

Step B: 17-Ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-2'-(3",4"-hydroxycylohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

To a solution of 17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-2'-(3",4"-di(tert-butyldimethylsiloxy)cyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (11.6 g) in methylenechloride (100 mL) was added a methanolic solution of p-toluenesulfonicacid (100 mL of a 10% solution w/v) and the mixture stirred at roomtemperature. After 30 minutes, the reaction was cooled to 0° C. andquenched by the careful addition of saturated sodium bicarbonatesolution. The mixture was extracted with ethyl acetate and the organicportion washed with brine, dried over magnesium sulfate, and theconcentrate purified by flash chromatography on silica gel (ethylacetate:hexane (3:2) to give the title compound (8.4 g)

¹ H NMR consistent with the desired structure.

Step C: 17-Ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-2'-(4"-hydroxy-3"-(tert-butyldimethylsiloxy)-cylohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !-octacos-18-ene-2,3,10,16-tetraone and

17-Ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-2'-(4"-(tert-butyldimethylsiloxy)-3"-hydroxycylohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

To a solution of 17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-2'-(3",4"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (8.17 g) in dry methylenechloride (92 mL) was added an excess of 2,6-lutidine (1.6 mL) and themixture was stirred at 0° C. on an ice bath. After 10 minutes,tert-butyldimethylsilyl trifluoromethanesulfonate (2.1 mL) was added viasyringe and the mixture allowed to warm slowly to room temperature.After 1 hour the reaction mixture was diluted with ethyl acetate,extracted from 1N hydrochloric acid, washed with water, saturated sodiumbicarbonate, brine, and the organic phase dried over magnesium sulfate.Purification of the concentrate by flash chromatography on silica gel(10% acetone in hexane) gave the title compounds (3" ether: 1.81 g, 4"ether: 1.20 g).

¹ H NMR consistent with the desired structure.

Step D: 17-Ethyl-1,14-dihydroxy-12-2'-(4"-(m-hydroxycinnamyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

Prepared essentially as described in Example 83 usingm-(tert-butyldimethylsiloxy)cinnamyl trichloroacetimidate as theelectrophile.

MASS (FAB) 916 (M+Li)

Partial ¹ H NMR δ: 7.22-6.67 (m, 5H); 6.52 (d J=16 Hz, 1H); 6.23 (dtJ=16, 6 Hz, 1H); 5.30M, 5.17m (brd J=3 Hz, 1H); 4.41 (d J=14 Hz, 1H).

EXAMPLE 91

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(3'",5'"-difluorocinnamyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

Prepared essentially as described in Example 90 using3,5-difluorocinnamyl trichloroacetimidate as the electrophile.

MASS (FAB) 936 (M+Li)

Partial ¹ H NMR δ: 6.90-6.58 (m, 3H); 6.51(d J=16 Hz, 1H); 6.38 (dtJ=16, 6 Hz, 1H); 5.30M, 5.17m (brd J=3 Hz, 1H); 4.41 (d J=4 Hz, 1H).

EXAMPLE 92

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(p-carboxybenzyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

Step A: 17-Ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-2'-(4"-(p-(tert-butyldimethylsiloxymethyl)-benzyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0.sup.4,9 !octacos-18-ene-2,3,10,16-tetraone

Prepared essentially as described in Example 44 usingp-(tert-butyldimethylsiloxymethyl)-benzyl trichloroacetimidate as theelectrophile.

¹ H NMR consistent with the desired structure.

Step B: 17-Ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-2'-(4"-(p-hydroxymethyl)-benzyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

To a solution of 17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-2'-(4"-(p-(tert-butyldimethylsiloxymethyl)-benzyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0.sup.4,9 !octacos-18-ene-2,3,10,16-tetraone (420 mg) inmethylene chloride (10 mL) was added a methanolic solution ofp-toluenesulfonic acid (10 mL of a 10% solution w/v) and the mixturestirred at room temperature. After 5 minutes, the reaction was cooled to0° C. and quenched by the careful addition of saturated sodiumbicarbonate solution. The mixture was extracted with ethyl acetate andthe organic portion washed with brine, dried over magnesium sulfate, andthe concentrate purified by flash chromatography on silica gel (ethylacetate:hexane (1:1+1% methanol) to give the title compound (316 mg).

¹ H NMR consistent with the desired structure.

Step C: 17-Ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-2'-(4"-(p-formylbenzyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

To a solution of 17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-2'-(4"-(p-hydroxymethyl)-benzyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,-25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (316 mg) in methylenechloride (6.0 mL) was added powdered 4 Å molecular sieves (20 mg)followed by 4-methylmorpholine-N-oxide (84.5 mg) andtetra-n-propylammonium perruthenate (5.5 mg), and the mixture stirred atroom temperature. After 15 minutes, the mixture was filtered through asmall silica gel column, washed with ethyl acetate, and the concentratedorganics purified by flash chromatography on silica gel (ethylacetate:hexane (1:1)+1% methanol) to give the title compound (282 mg).

¹ H NMR consistent with the desired structure.

Step D: 17-Ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-2'-(4"-(p-carboxybenzyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

To a solution of 17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-2'-(4"-(p-formylbenzyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (50 mg) in tert-butanol(1.0 mL) was added 2-methyl-2-butene (250 mL) followed by 0.5 mL of anaqueous solution of sodium chlorite (41 mg) and sodium dihydrogenphosphate (48 mg), and the mixture stirred at room temperature. After1.5 hours, the mixture was concentrated and redissolved in ethylacetate:hexane (1:1) and washed with water. The organic portion wasdried over sodium sulfate, and the concentrate purified by flashchromatography on silica gel (ethyl acetate:hexane (4:1) +1% methanol+0.5% acetic acid) to give the title compound (43 mg).

¹ H NMR consistent with the desired structure.

Step E: 17-Ethyl-1,14-dihydroxy-12-2'-(4"-(p-carboxybenzyl-oxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

Prepared essentially as described in Example 89 (Step B)

MASS (FAB) 933 (M+Li)

Partial ¹ H NMR δ: 8.04 (d J=8 Hz, 2H); 7.44 (d J=8 Hz, 2H); 5.30M,5.17m (brd J=3 Hz, 1H); 4.41 (d J=14 Hz, 1H); 4.73 (s, 2H).

EXAMPLE 93

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(m-carboxybenzyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

Prepared essentially as described in Example 92 usingm-(tert-butyldimethylsiloxy)cinnamyl trichloroacetimidate as theelectrophile.

MASS (FAB) 949 (M+Na)

Partial ¹ H NMR δ: 8.07 (s, 1H); 7.97 (d J=8 Hz, 1H); 7.60 (d J=8 Hz,1H); 7.41 (t J=8 Hz, 1H); 5.30M, 5.17m (brd J=3 Hz, 1H); 4.41 (d J=14Hz, 1H).

EXAMPLE 94

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(m-carbomethoxybenzyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

To a solution of 17-ethyl-1,14-dihydroxy-12-2'-(4"-(m-carboxybenzyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (7 mg) in methylenechloride:methanol (2:1,0.75 mL) at 0° C. was added a methylene chloridesolution of trimethylsilyldiazomethane (10% by weight) until a yellowcolored persisted. The mixture was then warmed to room temperature,concentrated in vacuo, and purified by flash chromatography on silicagel (acetone:hexane (1:2)) to give the title compound (5.5 mg).

MASS (FAB) 963 (M+Na)

Partial ¹ H NMR δ: 8.03 (d J=8 Hz, 2H); 7.46 (d J=8 Hz, 2H); 5.30M,5.17m (brd J=3 Hz, 1H); 4.41 (d J=14 Hz, 1H); 3.92(s, 3H).

EXAMPLE 95

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(m-isopropylcarboxamidobenzyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

Step A: 17-Ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-(12-2'-(4"-(m-isopropylcarboxamidobenzyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

To a solution of 17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-2'-(4"-(m-carboxybenzyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (50 mg) in methylenechloride (1.0 mL) was added4-benzotriazol-1-yloxytris(dimethylamino)phosphoniumhexafluoro-phosphate (BOP, 32 mg) followed by triethylamine (14 μL) andthe mixture stirred at room temperature. After 10 minutes,isopropylamine (8.0 μL) was added, and the reaction stirred at roomtemperature for 12 hours. At this time the mixture was concentrared andpurified by flash chromatography on silica gel (ethyl acetate:hexane(1:1)+1% methanol) to give the title compound (43 mg).

¹ H NMR consistent with the desired structure.

Step B: 17-Ethyl-1,14-dihydroxy-12-2'-(4"-(m-isopropylcarboxamidobenzyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

Prepared essentially as described in Example 89 (Step B).

MASS (FAB) 974 (M+Li)

Partial ¹ H NMR δ: 7.81 (s, 1H); 7.69 (d J=7 Hz, 1H); 7.44 (m, 2H); 6.00(d J=8 Hz, 1H); 4.75 (s, 2H); 5.30M, 5.17 m (brd J=3 Hz, 1H); 4.41 (dJ=14 Hz, 1H).

EXAMPLE 96

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(m-butylcarboxamidobenzyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

Prepared essentially as described in Examples 95 (Step A), 83 (Step B)using n-butyl amine as the nucleophile.

MASS (FAB) 988 (M+Li)

Partial ¹ H NMR δ: 7.82 (s, 1H); 7.70 (d J=7 Hz, 1H); 7.44 (m, 2H); 6.18(t J=5 Hz, 1H); 5.30M, 5.17m (brd J=3 Hz, 1H); 4.41 (d J=14 Hz, 1H).

EXAMPLE 97

17-Ethyl-1,14-dihydroxy-12-2'-(4"-acetamidoxy-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo 22.3.1.0⁴,9!octacos-18-ene-2,3,10,16-tetraone

Step A: 17-Ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-2'-(4"-carboxymethoxy-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

To a solution of 17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-2'-(4"-ethanaloxy-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !-octacos-18-ene-2,3,10,16-tetraone (311 mg) in tert-butanol(6.6 ml) and 2-methyl-2-butene (1.65 ml) was added sodium chlorite (273mg) and sodium dihydrogen phosphate (272 mg) in water (2.7 ml) slowly.After 2 hours, the solvent was removed in vacuo, and the resultingresidue was dissolved in water and acidified to pH 3 with 1N HCl. Theaqueous layer was extracted with ethyl acetate (3×10 ml), and thecombined organic portions washed with brine, dried over magenesiumsulfate and purified by flash chromatography on silica gel (2% methanolin methylene chloride followed by 2% methanol in methylene chloride+0.5%acetic acid) to give the title compound (255 mg).

¹ H NMR consistent with the desired structure.

Step B: 17-Ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-2'-(4"-acetamidoxy-3"-methoxycyciohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

To a solution of 17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-2'-(4"-carboxymethoxy-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (24.3 mg) in methylenechloride:N,N-dimethylformamide (4:1, 0.5 mL) was added an admixture of1-hydroxybenzotriazole hydrate (4.0 mg) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (6.7 mg) andthe mixture atirred at room temperature. After 30 minutes, ammoniumhydroxide (4.0 μL of a 25% aqueous solution) was added and the mixturestirred for an additional 4 hours. At this time, the solution wasfiltered over diatomaceous earth, diluted with ethyl acetate, andextracted with sodium bicarbonate. The organic portion was dried overmagnesium sulfate, concentrated in vacuo, and purified by flashchromatography on silica gel (ethyl acetate:hexane (1:1)+1% methanol,then (2:1)+1% methanol) to give the title compound (14 mg).

¹ H NMR consistent with the desired structure.

Step C: 17-Ethyl-1,14-dihydroxy-12-2'-(4"-acetamidoxy-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

Prepared essentially as described in Example 83 (Step B).

MASS (FAB) 872 (M+Na)

Partial ¹ H NMR δ: 7.79 (s, 2H); 5.30M, 5.17m (brd J=3 Hz, 1H); 4.41 (dJ=14 Hz, 1H).

EXAMPLE 98

17-Ethyl-1,14-dihydroxy-12-2'-(4"-carboxymethoxy-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 octacos-18-ene-2,3,10,16-tetraone

Prepared essentially as described in Example 89 (Step B).

MASS (FAB) 863 (M+2Li)

Partial ¹ H NMR δ: 5.24 (m, 2H); 5.02 (brd J=9 Hz, 1H); 4.94 (m, 1H);4.44 (m, 2H).

EXAMPLE 99

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(N-phenylacetamidoxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

Prepared essentially as described in Example 95 (Step A) from17-ethyl-1,14-dihydroxy-12-2'-(4"-carboxymethoxy-3"-methoxycyclohexyl)-1'-methylvinyl!23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone using aniline as thenucleophile.

MASS (FAB) 932 (M+Li)

Partial ¹ H NMR δ: 9.57 (brs, 1H); 7.61-7.05 (m, 5H); 5.26 (m, 2H); 4.42(m, 2H).

EXAMPLE 100

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(N-benzylacetamidoxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

Prepared essentially as described in Example 97 (Step B) from17-ethyl-1,14-dihydroxy-12-2'-(4"-carboxymethoxy-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone using benzylamine as thenucleophile.

MASS (FAB) 946 (M+Li)

partial ¹ H NMR δ: 8.14 (brs, 1H); 7.30 (m, 5H); 5.21 (m, 2H); 3.04 (s,2H).

EXAMPLE 101

17-Ethyl-1-hydroxy-12-2'-(4"-carboxymethoxy-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 octacos-18-ene-2,3,10,16-tetraone

Prepared essentially as described in Example 97 (Step A) from17-ethyl-1-hydroxy-12-2'-(4"-ethanaloxy-3"-methoxycyclohexyl)-1'-methylvinyl!-23,-25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone.

¹ H NMR consistent with the desired structure.

EXAMPLE 102

17-Ethyl-1-hydroxy-12-2'-(4"-(N-benzylamidoxymethoxy-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

Prepared essentially as described in Example 95 (Step A) usingbenzylamine as the nucleophile.

MASS (FAB) 930 (M+Li)

Partial ¹ H NMR δ: 8.19 (brs, 1H); 7.29 (m, 5H); 4.85 (brd J=8 Hz, 1H);4.55 (m, 2H).

EXAMPLE 103

17-Ethyl-1-hydroxy-12-2'-(4"-(N-methyltyrosine)amidoxy-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

Prepared essentially as described in Example 95 (Step A) using tyrosinemethyl ester hydrochloride as the nucleophile.

MASS (FAB) 1018 (M+Li)

Partial ¹ H NMR δ: 6.98 (m, 2H); 6.73 (m, 2H); 4.02 (m, 2H); 3.69 (s,3H).

EXAMPLE 104

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(m-methylphenyl)-2'"-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

Prepared essentially as described in Example 77 using m-methylphenylmagnesium bromide as the nucleophile.

MASS (FAB) 931 (M+Li)

Partial ¹ H NMR δ: 7.70 (m, 2H); 7.32 (m, 2H); 5.30M, 5.17m (brd J=3 Hz,1H); 4.41 (d J=14 Hz, 1H); 2.39 (s, 3H).

EXAMPLE 105

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(p-methylphenyl)-2'"-oxoethyloxy)-3-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

Prepared essentially as described in Example 77 using p-methylphenylmagnesium bromide as the nucleophile.

Partial ¹ H NMR δ: 7.82 (d J=8 Hz, 2H); 7.23 (d J=8 Hz, 2H); 5.30M,5.17m (brd J=3 Hz, 1H); 4.41 (d J=14 Hz, 1H); 2.33 (s, 3H).

EXAMPLE 106

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-phenyl-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,-10,16-tetraone

Prepared essentially as described in Example 77 (Steps A,C) using phenylmagnesium bromide as the nucleophile.

MASS (FAB) 919 (M+Li)

Partial ¹ H NMR δ: 7.32 (m, 5H); 5.30M, 5.17m (brd J=3 Hz, 1H); 4.41 (dJ=14 Hz, 1H); 3.08 (d J=3 Hz, 1H).

EXAMPLE 107

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(m-methylphenyl)-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

Prepared essentially as described in Example 77 (Steps A,C) usingm-methylphenyl magnesium bromide as the nucleophile.

MASS (FAB) 933 (M+Li)

Partial ¹ H NMR δ: 7.25-7.03 (m, 4H); 5.30M, 5.17 m (brd J=3 Hz, 1H);4.41 (d J=14 Hz, 1H); 2.32 (s, 3H).

EXAMPLE 108

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(m-ethylphenyl)-2'"-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

Prepared essentially as described in Examples 77 (Step A), 56, 77 (StepsB,C) using m-vinylphenyl magnesium bromide as the nucleophile.

MASS (FAB) 945 (M+Li)

Partial ¹ H NMR δ: 7.75 (s, 1H); 7.71 (d J=6 Hz, 1H); 7.37 (m, 2H);5.30M, 5.17m (brd J=3 Hz, 1H); 4.41 (d J=14 Hz, 1H); 2.68 (q J=8 Hz,2H); 1.22 (t J=8 Hz, 3H).

EXAMPLE 109

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-phenylethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

Step A: 17-Ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-2'-(4"-(2'"-phenyl-2'"-trifluoroacetoxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

To a solution of 17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-2'-(4"-(2'"-phenyl-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (23.3 mg) in methylenechloride (0.6 mL) was added triethylamine (12 μL) followed bytrifluoroacetic anhydride (6.4 μL) and N,N-dimethylaminopyridine (3 mg)and the mixture stirred at room temperature. After 15 minutes, thereaction was quenched by the addition of saturated sodium bicarbonatesolution, extracted with ethyl acetate, and the organics dried overmagnesium sulfate. Purification of the concentrate by flashchromatography on silica gel (ethyl acetate:hexane (1:3)+1% methanol)gave the title compound (5 mg).

¹ H NMR consistent with the desired structure.

Step B: 17-Ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-phenylethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

Prepared essentially as described in Examples 56 and 83

(Step B)

MASS (FAB) 919 (M+Na)

Partial ¹ H NMR δ: 7.30-7.22 (m, 5H); 5.30M, 5.17m (brd J=3 Hz, 1H);4.41 (d J=14 Hz, 1H).

EXAMPLE 110

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-phenyl-2'"-acetoxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3-10,16-tetraone

Prepared essentially as described in Examples 104 (Step A) and 83 (StepB) using acetic anhydride as the electrophile.

Partial ¹ H NMR δ: 7.33 (m, 5H); 6.03 (m, 1H); 5.30M, 5.17m (brd J=3 Hz,1H); 4.41 (d J=14 Hz, 1H); 2.09 (s, 3H).

EXAMPLE 111

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-morpholinoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

Step A: 17-Ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-2'-(4"-(2'"-methanesulfonyloxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

To a solution of 17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-2'-(4"-(2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (80.8 mg) in methylenechloride (1.0 mL) was added triethylamine (23 μL) followed bymethanesulfonyl chloride (7.2 μL) and the mixture stirred at roomtemperature. After 10 minutes, the reaction was quenched by the additionof saturated sodium bicarbonate solution, extracted with ethyl acetate,and the organic portion dried over magnesium sulfate. Purification ofthe concentrate by flash chromatography on silica gel (ethylacetate:hexane (2:1)+1% methanol) gave the title compound (74 mg).

¹ H NMR consistent with the desired structure.

Step B: 17-Ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-2'-(4"-(2'"-morpholinoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

To a solution of 17-ethyl-1-hydroxy-14-(tertobutyldimethylsiloxy)-12-2'-(4"-(2'"-methanesulfonyloxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (26.5 mg) in drytetrahydofuran (0.3 mL) was added 200 μL of a sodium morpholine solution(prepared by addition of 10 μL morpholine to a suspension of 2.3 mgsodium hydride in 0.5 mL of tetrahydrofuran) and the mixture heated to70° C. After 6 hours, the mixture is cooled to room temperature andquenched by the addition of saturated ammonium chloride solution,extracted with ethyl acetate, and the organic portion dried overmagnesium sulfate. Purification of the concentrate by flashchromatography on silica gel (ethyl acetate:hexane (2:1)+1% methanol,then 2% ammonium hydroxide, 5% methanol, in methylene chloride) gave thetitle compound (10 mg).

¹ H NMR consistent with the desired structure.

Step C: 17-Ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-morpholinoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 octacos-18-ene-2,3,10,16-tetraone

Prepared essentially as described in Example 83 (Step B).

MASS (FAB) 911 (M+Li)

Partial ¹ H NMR δ: 5.30M, 5.17m (brd J=3 Hz, 1H); 4.41 (d J=14 Hz, 1H);3.71 (m, 4H); 2.56 (m, 4H).

EXAMPLE 112

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(naphth-2-yl-methyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

Prepared essentially as described in Example 44 using naphth-2-ylmethyltrichloroacetimidate as the electrophile and diethyl ether as thesolvent.

MASS (FAB) 938 (M+Li)

¹ H NMR consistent with the desired structure.

EXAMPLE 113

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(4",5"-methylenedioxybenzyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

Prepared essentially as described in Example 44 using4,5-methylenedioxybenzyl trichloroacetimidate as the electrophile.

MASS (FAB) 932 (M+Li)

Partial ¹ H NMR δ: 6.88 (s, 1H); 6.78 (d J=7 Hz, 1H); 6.74 (d J=7 Hz,1H); 5.92 (s, 2H); 4.59 (d J=8 Hz, 1H); 4.52 (d J=8 Hz, 1H).

EXAMPLE 114

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(4'"-N,N,-dimethylaminophenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

Prepared essentially as described in Example 1 usingtri-(p-N,N-dimethylphenyl)bismuth diacetate as the arylating agent.

MASS (FAB) 917 (M+Li)

Partial ¹ H NMR δ: 6.87 (d J=10 Hz, 2H); 6.68 (d J=10 Hz, 2H); 2.83 (s,6H).

EXAMPLE 115

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(3'"-fluorophenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

Prepared essentially as described in Example 1 usingtri-(m-fluorophenyl)bismuth diacetate as the arylating agent.

MASS (FAB) 892 (M+Li)

¹ H NMR consistent with the desired structure.

EXAMPLE 116

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(3'"-(2""-dioxolanylphenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

Prepared essentially as described in Example 1 usingtris(3-(2'-dioxolanyl)phenyl)bismuth diacetate as the arylating agent.

MASS (FAB) 946 (M+Li)

Partial ¹ H NMR δ: 7.3-6.9 (m, 4H); 5.78 (s, 1H); 4.13-3.97 (m, 4H).

EXAMPLE 117

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(3'"-formylphenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

Prepared essentially as described in Example 90 (Step B) from17-Ethyl-1,14-dihydroxy-12-2'-(4"-(3'"-(2""-dioxolanylphenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone.

MASS (FAB) 902 (M+Li)

¹ H NMR consistent with the desired structure.

EXAMPLE 118

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(3'"-carboxyphenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

Prepared essentially as described in Example 92 (Step D) from17-ethyl-1,14-dthydroxy-12-2'-(4"-(3'"-formylphenyloxy)-3"-methoxycyclohexyl)-1'methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone.

¹ H NMR consistent with the desired structure.

EXAMPLE 119

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(3'",4'"-dimethoxyphenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

Prepared essentially as described in Example 1 usingtris(3,4-dimethoxyphenyl) bismuth acetate as the alkylating agent.

MASS (FAB) 934 (M+Li)

Partial ¹ H NMR δ: 6.72 (d J=8 Hz, 1H); 6.56 (d J=2.5 Hz, 1H); 6.47 (ddJ=8, 2.5 Hz, 1H); 4.57 (brd J=8 Hz, 1H); 4.39 (brd J=14.5 Hz, 1H); 3.79(s, 3H); 3.77 (s, 3H).

EXAMPLE 120

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(4'"-trifluoromethylphenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

Prepared essentially as described in Example 1 usingtris(4-trifluoromethylphenyl) bismuth acetate as the alkylating agent.

MASS (FAB) 942 (M+Li)

Partial ¹ H NMR δ: 7.48 (d J=9.5 Hz, 2H); 6.98 (d J=9.5 Hz, 2H); 4.59(brd J=5 Hz, 1H); 4.41 (brd, J=14.5 Hz, 1H).

EXAMPLE 121

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(3",5"-bis(trifluoromethyl)phenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

Prepared essentially as described in Example 1 usingtris(3,5-bis(trifluoromethyl)phenyl)bismuth acetate as the alkylatingagent.

MASS (FAB) 1010 (M+Li)

Partial ¹ H NMR δ: 7.39 (s, 1H); 7.34 (s, 2H); 4.59 (brd J=5 Hz, 1H);14.4(brd J=14.5 Hz, 1H).

EXAMPLE 122

A. 17-Ethyl-1-hydroxy-12-2'-(4"-(4'"-methylphenyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !-octacos-18-ene-2,3,10,16-tetraone and

B. 17-Ethyl-1-hydroxy-12- 2'-(4"-hydroxy-3"-(4'"-methylphenyloxy)cyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

Prepared essentially as described in Example 2 from17-ethyl-1-hydroxy-12-2'-(3",4"-dihydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-22.3.1.0.sup.4,9 !octacos-18-ene-2,3,10,16-tetraone usingtri-(p-methylphenyl)bismuth diacetate as the alkylating agent.

A. (4"-ether)

Partial ¹ H NMR δ: 7.07 (d J=8.4 Hz, 2H); 6.83 (d J=8.4 Hz, 2H); 5.2-4.8(m, 3H); 4.75(s, 1H).

B. (3"-ether): MASS (FAB) 859 (M+Li)

Partial ¹ H NMR δ: 7.07 (d J=8.4 Hz, 2H); 6.82 (d J=8.4 Hz, 2H);5.15-4.8 (m, 3H)

EXAMPLE 123

A. 17-Ethyl-1-hydroxy-12-2'-(4"-(4'"-hydroxyphenyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone and

B. 17-Ethyl-1-hydroxy-12-2'-(4"-hydroxy-3"-(4'"-hydroxyphenyloxy)cyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

Prepared essentially as described in Examples 122 and 90 (Step B) usingtris-(p-(tert-butyldimethylsiloxy)phenyl)bismuth diacetate as thealkylating agent.

A. (4"-ether)

MASS (FAB) 862 (M+Li)

Partial ¹ H NMR δ: 6.80 (d J=9 Hz, 2H); 6.72 (d J=9 Hz, 2H); 5.24 (brs,1H); 5.1-4.8(m, 3H).

B. (3"-ether)

MASS (FAB) 862 (M+Li)

Partial ¹ H NMR δ: 6.80 (d J=9 Hz, 2H); 6.72 (d J=9 Hz, 2H); 5.37 (brs,1H); 5.1-4.9 (m, 3H).

EXAMPLE 124

A. 17-Ethyl-1-hydroxy-12-2'-(4"-(4'"-hydroxymethylphenyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone and

B. 17-Ethyl-1-hydroxy-12- 2'-(4"-hydroxy-3"-(4'"-hydroxymethylphenyloxy)cyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

Prepared essentially as described in Examples 122 and 90 (Step B) usingtris-(p-(tert-butyldimethylsiloxymethyl)phenyl)bismuth diacetate as thealkylating agent.

A. (4"-ether)

MASS (FAB) 875 (M+Li)

Partial ¹ H NMR δ: 7.26 (d J=10.2 Hz, 2H); 6.90 (d J=10.2 Hz, 2H);5.1-4.8 (m, 3H); 4.59 (s, 2H).

B. (3"-ether)

MASS (FAB) 875 (M+Li)

Partial ¹ H NMR δ: 7.26 (d J=9.75 Hz, 2H); 6.91 (d J=9.75 Hz, 2H);5.1-4.8 (m, 3H); 4.59 (brs, 2H).

EXAMPLE 125

17-Ethyl-1-hydroxy-12-2'-(4"-hydroxy-3"-(4'"-formylphenyloxy)cyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

Prepared essentially as described in Example 92 (Step C) from17-ethyl-1-hydroxy-12- 2'-(4"-hydroxy-3"-(4'"-hydroxymethylphenyloxy)cyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone.

Partial ¹ H NMR δ: 9.80 (s, 1H); 7.83 (d J=8.5 Hz, 2H); 7.01 (d J=8.5Hz, 2H); 5.20-4.95 (m, 2H); 4.87 (d J=9.4 Hz, 1H).

EXAMPLE 126

A. 17-Ethyl-1-hydroxy-12-2'-(4"-(4'"-N,N-dimethylaminophenyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone and

B. 17-Ethyl-1-hydroxy-12-2'-(4"-hydroxy-3"-(4'"-N,N-dimethylaminophenyloxy)cyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0.sup.4,9 !octacos-18-ene-2,3,10,16-tetraone

Prepared essentially as described in Example 122 usingtri(p-N,N-dimethylaminophenyl) bismuth diacetate as the alkylatingagent.

A. (4"-ether)

Partial ¹ H NMR δ: 6.86 (d J=9.06 Hz, 2H); 6.68 (d J=9.06 Hz, 2H);5.15-4.80(m, 3H).

B. (3"-ether)

Partial ¹ H NMR δ: 6.87 (d J=7.3 Hz, 2H); 6.68 (d J=7.3 Hz, 2H);5.1-4.80 (m, 3H).

EXAMPLE 127

A. 17-Ethyl-1-hydroxy-12-2'-(4"-phenyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone and

B. 17-Ethyl-1-hydroxy-12-2'-(4"-hydroxy-3"-phenyloxy)cyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

Prepared essentially as described in Example 122 usingtris(phenyl)bismuth diacetate as the alkylating agent.

A. (4"-ether)

MASS (FAB) 860 (M+Na)

Partial ¹ H NMR δ: 7.25 (m, 2H); 6.92 (m, 3H); 5.10M, 4.85m (t J=9 Hz,2H); 5.00 (m, 2H).

B. (3"-ether)

MASS (FAB) 860 (M+Na)

Partial ¹ H NMR δ: 7.25 (m, 2H); 6.93 (m, 3H); 5.07 (t J=9 Hz, 2H); 4.97(m, 2H); 4.82 (m, 2H); 4.52 (d J=5 Hz, 2H).

EXAMPLE 128

A. 17-Ethyl-1-hydroxy-12-2'-(4"-(4'"-methoxyphenyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone and

B. 17-Ethyl-1-hydroxy-12-2'-(4"-hydroxy-3"-(4'"-methoxyphenyloxy)cyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

Prepared essentially as described in Example 122 usingtris-(p-methoxyphenyl)bismuth diacetate as the alkylating agent.

A. (4"-ether)

MASS (FAB) 875 (M+Li)

B. (3"-ether)

MASS (FAB) 875 (M+Li)

Partial ¹ H NMR δ: 6.87 (m, 2H); 6.78 (m, 2H); 5.05 (t J=9 Hz, 2H); 3.72(s, 3H).

EXAMPLE 129

A. 17-Ethyl-1-hydroxy-12-2'-(4"-(3'"-methoxyphenyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone and

B. 17-Ethyl-1-hydroxy-12-2'-(4"-hydroxy-3"-(3'"-methoxyphenyloxy)cyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

Prepared essentially as described in Example 122 usingtris(m-methoxyphenyl)bismuth diacetate as the alkylating agent.

A. (4"-ether)

MASS (FAB) 875 (M+Li)

Partial ¹ H NMR δ: 7.13 (t J=10 Hz, 1H); 6.51 (m, 3H); 5.00 (m, 4H);3.72 (s, 3H).

B. (3"-ether)

MASS (FAB) 875 (M+Li)

Partial ¹ H NMR δ: 7.14 (t J=10 Hz, 1H); 6.49 (t J=10 Hz, 3H); 4.52 (dJ=5 Hz, 1H); 4.38m; 4.32M (s, 1H); 3.75 (s, 3H).

EXAMPLE 130

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-phenyl-2'"-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

Step A: 17-Ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-2'-(4"-(2'"-phenyl-2'"-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

To a solution of 17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (500 mg) and rhodiumacetate (5 mg, 2 mol %) in dichloromethane (4 ml) was addedα-diazoacetophenone (159 mg, 2 eq.) in dichloromethane (2 ml) dropwise.The reaction mixture was stirred for 15 minutes after the addition andthen filtered through a silica gel pad washing with ethyl acetate. Thefiltrate was concentrated and purified by column chromatography onsilica gel eluting with 60% hexane:40% ethyl acetate to give the desiredproduct (188 mg).

Step B: 17-Ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-phenyl-2'"-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

To a solution of the product from Step A (188 mg) in THF (2.8 ml) wasadded hydrogen fluoride/pyridine and the reaction mixture stirred atroom temperature for 24 hours. The reaction was then quenched by theaddition of saturated aqueous sodium bicarbonate and extracted intoethyl acetate. The organic phase was dried with magnesium sulphate andconcentrated. The crude material was purified by column chromatographyon silica gel eluting with 50% hexane:50% ethyl acetate to give thetitle compound (102 mg).

Partial ¹ H NMR (400 MHz, CDCl₃) δ: 7.91 (2H, d, J=7.2 Hz); 7.53 (1H, t,J=7.2 Hz); 7.43 (1H, t, J=7.2 Hz); 5.3 (1H major, d, J=2 Hz); 5.17 (1Hminor, d, J=2 Hz); 4.98 (4H, m), 4.82 (1H minor, s); 4.59 (1H, d, J=4.8Hz); 4.4 (1H, d, J=14 Hz); 4.21 (1H major, s).

EXAMPLE 131

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-p-t-butylphenyl-2'"-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

The title compound was prepared essentially as described in Example 130using p-t-butylbenzoyl diazomethane as the reagent in Step A.

MS(FAB) 973 (M+Li)

Partial ¹ H NMR (400 MHz, CDCl₃) δ: 7.87 (2H, d, J=8.3 Hz); 7.43 (2H, d,J=8.3 Hz); 5.3 (1H major, d, J=2 Hz); 5.17 (1H minor, d, J=2 Hz); 4.98(4H, m), 4.82 (1H minor, s); 4.59 (1H, d, J=4.8 Hz); 4.4 (1H, d, J=14Hz); 4.21 (1H major, s).

EXAMPLE 132

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-m-nitrophenyl-2'"-oxoethyloxy)-3"-methoxycyclohexyl)-1-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

The title compound was prepared essentially as described in Example 130using m-nitrobenzoyl diazomethane as the reagent in Step A.

MS(FAB) 961 (M+Li)

Partial ¹ H NMR (400 MHz, CDCl₃) δ: 8.8 (1H, s), 8.4 (1H, dd, J=8 Hz);8.3 (1H, d, J=8 Hz); 7.66 (1H, t, J=8 Hz); 5.3 (1H major, s); 5.18 (1Hminor, s); 5.92 (4H, m); 4.82 (1H minor, s); 4.59 (1H, d, J=4.8 Hz); 4.4(1H, d, J=14 Hz); 4.21 (1H major, s).

EXAMPLE 133

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-m-isopropoxyphenyl-2'"-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

The title compound was prepared essentially as described in Example 130using m-isopropoxybenzoyl diazomethane as the reagent in Step A.

MS(FAB) 974 (M+Li)

Partial ¹ H NMR (400 MHz, CDCl₃) δ: 7.43 (2H, m); 7.31 (1H, t, J=7.1Hz); 7.06 (1H, d, J=7.1 Hz); 5.3 (1H major, d, J=2 Hz); 5.17 (1H minor,d, J=2 Hz); 4.98 (4H, m); 4.82 (1H minor, s); 4.59 (2H, m); 4.4 (1H, d,J=14 Hz); 4.21 (1H major, s).

EXAMPLE 134

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-m-bromophenyl-2'"-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

The title compound was prepared essentially as described in Example 130using m-bromobenzoyl diazomethane as the reagent in Step A.

Partial ¹ H NMR (400 MHz, CDCl₃) δ: 8.08 (1H, s); 7.86 (1H, d, J=7.5Hz); 7.69 (1H, d, J=7.5 Hz); 5.3 (1H major, d, J=2 Hz); 5.17 (1H minor,d, J=2 Hz); 4.92 (5H, m); 4.59 (2H, m), 4.4 (1H, d, J=13.6 Hz); 4.21 (1Hmajor, s).

EXAMPLE 135

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-m-fluorophenyl-2'"-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

The title compound was prepared essentially as described in Example 130using m-fluorobenzoyl diazomethane as the reagent in Step A.

MS(FAB) 934 (M+Li)

Partial ¹ H NMR (400 MHz, CDCl₃) δ: 7.7 (1H, d, J=7.7 Hz); 7.64 (1H, d,J=9.5 Hz); 7.41 (1H, q, J=5.5 Hz); 7.23 (1H, m); 5.3 (1H major, s); 5.18(1H minor, s); 4.9 (4H, m); 4.82 (1H minor, s); 4.59 (1H, d, J=4.8 Hz);4.4 (1H, d, J=14 Hz); 4.21 (1H major, s).

EXAMPLE 136

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-m-chloromethylphenyl-2'"-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

The title compound was prepared essentially as described in Example 130using m-chloromethylbenzoyl diazomethane as the reagent in Step A.

MS(FAB) 964 (M+Li)

Partial ¹ H NMR (400 MHz, CDCl₃) δ: 7.93 (1H, s); 7.87 (1H, d, J=7 Hz);7.58 (1H, d, J=7 Hz); 7.43 (1H, t, J=7 Hz); 5.3 (1H major, s); 5.18 (1Hminor, s); 4.9 (4H, m); 4.82 (1H minor, s); 4.60 (2H, s); 4.58 (1H, d,J=4.8 Hz); 4.40 (1H, d, J=14 Hz); 4.21 (1H major, s).

EXAMPLE 137

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-m-cyanophenyl-2'"-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

The title compound was prepared essentially as described in Example 130using m-cyanobenzoyl diazomethane as the reagent in Step A.

MS(FAB) 941 (M+Li)

Partial ¹ H NMR (400 MHz, CDCl₃) δ: 8.35 (1H, s); 8.22 (1H, d, J=3 Hz);7.85 (1H, d, J=3 Hz); 7.62 (1H, t, J=3 Hz); 5.34 (1H major, s); 5.21 (1Hminor, s); 5.04 (2H, m); 4.90 (2H, m); 4.61 (1H, d, J=6 Hz); 4.44 (1H,d, J=13 Hz); 4.25 (1H, s).

EXAMPLE 138

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-m,m-difluorophenyl-2'"-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

The title compound was prepared essentially as described in Example 130using m,m-difluorobenzoyl diazomethane as the reagent in Step A.

MS(FAB) 952 (M+Li)

Partial ¹ H NMR (400 MHz, CDCl₃) δ: 7.54 (2H, d, J=3 Hz); 7.1 (1H, m);5.33 (1H major, s); 5.20 (1H minor, s); 5.60 (1H major, d, J=9 Hz); 5.02(1H, m); 4.86 (2H, m); 4.60 (1H, d, J=5 Hz); 4.24 (1H, s).

EXAMPLE 139

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-m,m-dimethylphenyl-2'"-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

The title compound was prepared essentially as described in Example 130using m,m-dimethylbenzoyl diazomethane as the reagent in Step A.

MS(FAB) 939 (M+1)

Partial ¹ H NMR (400 MHz, CDCl₃) δ: 7.50 (2H, s), 7.18 (1H, s), 5.30 (1Hmajor, d, J=1.8 Hz); 5.16 (1H minor, d, J=1.4 Hz); 4.98 (4H, m); 4.80(1H minor, s); 4.57 (1H, d, J=5.0 Hz); 4.40 (1H, d, J=12.5 Hz); 4.21 (1Hmajor, s).

EXAMPLE 140

-Ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-m-chlorophenyl-2'"-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

The title compound was prepared essentially as described in Example 130using m-chlorobenzoyl diazomethane as the reagent in Step A.

MS(FAB) 950 (M+Li)

Partial ¹ H NMR (400 MHz, CDCl₃) δ: 7.91 (1H, s); 7.8 (1H, d, J=6.9 Hz);7.52 (1H, m); 7.38 (1H, t, J=7.5 Hz); 5.3 (1H major, s); 5.18 (1H minor,s); 4.9 (4H, m); 4.82 (1H minor, s); 4.59 (1H, d, J=4.8 Hz), 4.4 (1H, d,J=14 Hz); 4.21 (1H major, s).

EXAMPLE 141

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-m-triflouromethylphenyl-2'"-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

The title compound was prepared essentially as described in Example 130using m-trifloromethylbenzoyl diazomethane as the reagent in Step A.

MS(FAB) 984.1 (M+Li)

Partial ¹ H NMR (400 MHz, CDCl₃) δ: 8.21 (1H, s); 8.13 (1H, d, J=7.7Hz); 7.80 (1H, J=7.7 Hz); 7.59 (1H, t, J=7.7 Hz); 5.30 (1H major, d,J=2.0 Hz); 5.17 (1H minor, d, J=1.8 Hz); 4.97 (4H, m); 4.81 (1H minor,s); 4.57 (1H, d, J=4.4 Hz); 4.40 (1H, d, J=12.4 Hz); 4.22 (1H major, s).

EXAMPLE 142

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(2-naphthyl)-2'"-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

The title compound was prepared essentially as described in Example 130using 2-naphthoyl diazomethane as the reagent in Step A (¹ H NMR wasconsistent with the desired structure).

EXAMPLE 143

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-phenyl-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatri-cyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

Step A: 17-Ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-2'-(4"-(2'"-phenyl-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

To a solution of 17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-2'-(4"-(2'"-phenyl-2'"-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (350 mg) in THF (6.2 ml)at -78° C. was added L-Selectride (342 μl, 1 eq) dropwise over 30minutes. The reaction was stirred for a further 15 minutes afteraddition and then quenched by pouring into saturated aqueous ammoniumchloride solution and extracted into ethyl acetate. The organic phasewas dried with magnesium sulphate and concentrated. The crude materialwas purified by column chromatography on silica gel eluting with 60%hexane:40% ethyl acetate to give the desired product (216 mg).

Step B: 17-Ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-phenyl-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

To a solution of the product from Step A (29 mg) in THF (400 μl) wasadded hydrogen fluoride/pyridine and the reaction mixture stirred atroom temperature for 24 hours. The reaction was then quenched by theaddition of saturated aqueous sodium bicarbonate and extracted intoethyl acetate. The organic phase was dried with magnesium sulphate andconcentrated. The crude material was purified by column chromatographyon silica gel eluting with 70% hexane:30% ethyl acetate to give thetitle compound (11 mg).

MS(FAB) 934 (M+Na)

Partial ¹ H NMR (400 MHz, CDCl₃) δ: 7.32 (5H, m); 5.30 (1H major, s);5.18 (1H minor, s); 5.0 (3H, m); 4.87 (2H, m); 4.65 (1H, m); 4.59 (1H,d, J=5.5 Hz); 4.4 (1H, d, J=14 Hz); 4.21 (1H major, s).

EXAMPLE 144

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-m-methylphenyl-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

The title compound was prepared essentially as described in Example 143.

Partial ¹ H NMR (400 MHz, CDCl₃) δ: 7.15 (4H, m); 5.3 (1H major, s);5.18 (1H minor, s); 5.0 (3H, m); 4.82 (2H, m); 4.59 (1H, d, J=5.5 Hz);4.4 (1H, d, J=14 Hz); 4.21 (1H major, s).

EXAMPLE 145

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-m-fluorophenyl-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

The title compound was prepared essentially as described in Example 143.

MS(FAB) 936 (M+Li)

Partial ¹ H NMR (400 MHz, CDCl₃) δ: 7.26 (1H, m); 7.1 (2H, m); 6.92 (1H,m); 5.3 (1H major, s); 5.18 (1H minor, s); 5.0 (3H, m); 4.85 (2H, m);4.78 (1H minor, br s); 4.59 (1H, d, J=5.5 Hz); 4.4 (1H, d, J=14 Hz);4.21 (1H major, s).

EXAMPLE 146

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-m-chloromethylphenyl-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-22.3.1.0⁴,9 !octacos-18ene-2,3,10,16-tetraone

The title compound was prepared essentially as described in Example 143.

MS(FAB) 966 (M+Li)

Partial ¹ H NMR (400 MHz, CDCl₃) δ: 7.40 (1H, s); 7.29 (3H, m; 5.3 (1Hmajor, d, J=2 Hz); 5.17 (1H minor, d, J=2 Hz); 5.01 (2H, m); 4.88 (1H,m); 4.58 (1H, s); 4.41 (1H, d, J=13.5 Hz).

EXAMPLE 147

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-m,m-difluorophenyl-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-22.3.1.0⁴,9 !octacos-18ene-2,3,10,16-tetraone

The title compound was prepared essentially as described in Example 143.

MS(FAB) 948 (M+1)

Partial ¹ H NMR (400 MHz, CDCl₃) δ: 6.88 (2H, d, J=6.5 Hz); 6.67 (1H, t,J=6.5 Hz); 5.30 (1H major, d, J=1.8 Hz); 5.17 (1H minor, d, J=1.8 Hz);5.0 (3H, m); 4.82 (2H, m); 4.57 (1H, d, J=5.3 Hz); 4.4 (1H, d, J=14 Hz);4.21 (1H, s).

EXAMPLE 148

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-m,m-dimethylphenyl-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

The compound was prepared essentially as described in Example 143.

MS(FAB) 941 (M+1)

Partial ¹ H NMR (400 MHz, CDCl₃) δ: 6.96 (2H, s); 6.88 (1H); 5.30 (1Hmajor, d, J=1.8 Hz); 5.17 (1H minor, d, J=1.6 Hz); 5.02 (2H, m); 4.86(1H minor, s); 4.79 (1H, d, J=9.9 Hz); 4.58 (1H, d, J=5.2 Hz); 4.41 (1H,d, J=14.1 Hz); 4.22 (1H major, s).

EXAMPLE 149

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-m-chlorophenyl-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo- 22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

The title compound was prepared essentially as described in Example 143.

MS(FAB) 946 (M+H)

Partial ¹ H NMR (400 MHz, CDCl₃) δ: 7.38 (1H, s); 5.3 (1H major, s);5.18 (1H minor, s); 5.0 (3H, m), 4.73 (2H, m); 4.58 (1H, d, J=5.2 Hz);4.4 (1H, d, J=14 Hz); 4.22 (1H major, s).

EXAMPLE 150

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-m-trifluoromethylphenyl-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

The title compound was prepared essentially as described in Example 143.

MS(FAB) 986.1 (M+Li)

Partial ¹ H NMR (400 MHz, CDCl₃) δ: 7.70 (1H, s); 7.55 (2H, d, J=7.8Hz); 7.47 (1H, d, J=7.8 Hz); 5.35 (1H major, d, J=2.3 Hz); 5.22 (1Hminor, d, J=0.9 Hz); 5.05 (2H, m); 4.95 (1H, d, J=9.9 Hz); 4.88 (1Hminor, s); 4.62 (1H, d, J=4.8 Hz); 4.45 (1H, d, J=12.5 Hz); 4.26 (1Hmajor, s).

EXAMPLE 151

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(2-naphthyl)-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

Step A: 17-Ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-2'-(4"-(2'"-(2-naphthyl)-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

To a stirred solution of17-ethyl-1-hydroxy-14-(t-butyldimethylsilyloxy)-12-2'-(4"-ethanaloxy-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (1.0 g) in THF (10 mL) at-50° C. was added a solution of 2-naphthyl magnesium bromide (0.5M inTHF). The solution was stirred for 0.5 hr then quenched by addition ofaqueous NH₄ Cl solution and the product extracted 2× with CH₂ Cl₂. Theextracts were combined, dried with Na₂ SO₄, filtered and concentrated invacuo. Purification of the residue by column chromatography followed bypreparative TLC afforded 332 mg of the title compound as a colorlesssolid.

Step B: 17-Ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(2-naphthyl)-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

The product from Step A was deprotected with HF/pyridine as described inStep B from above to afford 190 mg of the title compound as a colorlesssolid (¹ H NMR was consistent with the desired structure).

EXAMPLE 154

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-phenyl-2'"-benzyloxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo 22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

Step A: 17-Ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-2'-(4"-(2'"-phenyl-2'"-benzyloxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !-octacos-18-ene-2,3,10,16-tetraone

To a solution of 17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-2'-(4"-(2'"-phenyl-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (40 mg) in cyclohexane(0.8 ml) and dichloromethane (0.4 ml) was added2,2,2-benzyltrichloroacetimidate at 0° C. followed by triflic acid. Thereaction was allowed to warm to room temperature and stir for 1.5 hoursafter which time it was poured into saturated aqueous sodium bicarbonatesolution and extracted into ethyl acetate. The organic extracts weredried (MgSO₄) and concentrated and the crude material was purified bycolumn chromatography on silica gel eluting with 65% hexane:35% ethylacetate to give the desired product (22 mg).

Step B: 17-Ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-phenyl-2'"-benzyloxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

To a solution of the product from Step A (22 mg) in THF (100 μl) wasadded hydrogen fluoride/pyridine and the reaction stirred at roomtemperature for 6 hours. The reaction was then quenched by the additionof saturated aqueous sodium bicarbonate and extracted into ethylacetate. The organic phase was dried with magnesium sulphate andconcentrated. The crude material was purified by column chromatographyon silica gel eluting with 50% hexane:50% ethyl acetate to give thetitle compound (15 mg).

MS(FAB) 1002 (M+H)

partial ¹ H NMR (400 MHz, CDCl₃) δ: 7.30 (10H, m); 5.30 (1H major, s);5.16 (1H minor, s); 5.0 (2H, m); 4.85 (1H minor, s); 4.53 (3H, m); 4.38(2H, m); 4.21 (1H major, s).

EXAMPLE 155

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-phenyl-2'"-allyloxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

The title compound was prepared essentially as described in Example 154using allyltrichloroacetimidate as the reagent in Step A.

MS(FAB) 951 (M⁺)

partial ¹ H NMR (400 MHz, CDCl₃) δ: 7.30 (5H, m), 5.88 (1H, ddd, J=28,10 and 5.3 Hz); 5.30 (1H major, s); 5.22 (1H, d, J=18 Hz); 5.16 (1Hminor, s); 5.1 (1H, d, J=8.6 Hz); 5.0 (2H, m); 4.83 (1H minor, s); 4.56(1H, s); 4.48 (1H, dd, J=7 and 4.6 Hz); 4.40 (1H, d, J=14 Hz); 4.20 (1Hmajor, s).

EXAMPLE 156

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-phenyl-2'"-methoxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !-octacos-18-ene-2,3,10,16-tetraone

Step A: 17-Ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-2'-(4"-(2'"-phenyl-2'"-methoxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

To a solution of 17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-2'-(4"-(2'"-phenyl-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (27 mg) in methyl iodide(0.5 ml) under nitrogen atmosphere was added silver oxide and thereaction was stirred at room temperature for 48 hours. The reaction wasthen diluted with ethyl acetate and filtered through a silica gel pad.The filtrate was concentrated and purified by column chromatography onsilica gel eluting with 60% hexane:40% ethyl acetate to give the desiredcompound (12.6 mg).

Step: 17-Ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-phenyl-2'"-methoxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

The title compound was prepared essentially as described in Example 154,Step B to yield 5 mg.

MS(FAB) 932 (M+Li)

partial ¹ H NMR (400 MHz, CDCl₃) δ: 7.30 (5H, m); 5.88 (1H, ddd, J=28,10 and 5.3 Hz); 5.30 (1H major, s); 5.22 (1H, d, J=18 Hz); 5.16 (1Hminor, s); 5.1 (1H, d, J=8.6 Hz); 5.0 (2H, m); 4.83 (1H minor, s); 4.56(1H, s); 4.48 (1H, dd, J=7 and 4.6 Hz); 4.40 (1H, d, J=14 Hz); 4.20 (1Hmajor, s).

EXAMPLE 157

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-phenyl-2'"-aminoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

Step A: 17-Ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-2'-(4"-(2'"-phenyl-2'"-azidoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

To a solution of 17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-2'-(4"-(2'"-phenyl-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (35 mg) indichloromethane (1 ml) at -10° C. was added triethylamine (14 μl)followed by methane sulphonyl chloride (8 μl) and the reation stirredfor 30 minutes. The reaction was concentrated and the residue wasdissolved in DMF (1 ml). Sodium azide (22 mg) was added and the reactionwas heated to 60° C. for 45 minutes before being poured into brine andextracted with ethyl acetate. The organic extracts were dried (MgSO₄),concentrated and purified by column chromatography on silica gel elutingwith 60% hexane:40% ethyl acetate to give the desired compound (27 mg).

Step B: 17-Ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-phenyl-2'"-aminoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-1,8-ene-2,3,10,16-tetraone

To a solution of the product from Step A (27 mg) in wet benzene (0.5 ml)was added triphenyl phosphine (15 mg) and the reaction heated to 60° C.for 2 hours. The reaction mixture was concentrated, dissolved in THF(200 μl) and treated with hydrogen fluoride/pyridine for 24 hours atroom temperature. The reaction was quenched with saturated aqueoussodium bicarbonate solution and extracted into ethyl acetate. The crudematerial was purified by preparative plate chromatography (20 cm×20 cm,500 microns) eluting with 90% dichloromethane: 10% methanol+1% ammoniumhydroxide to give the title compound (9 mg).

MS(FAB) 910 (M⁺)

partial ¹ H NMR (400 MHz, CDCl₃) δ: 7.30 (5H, m); 5.30 (1H major, s);5.18 (1H minor, s); 5.0 (3H, m); 4.59 (1H, d, J=5.5 Hz); 4.4 (1H, d,J=14 Hz); 4.21 (1H major, s).

EXAMPLE 158

17-Ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-phenyl-2'"-oxoethloxy)-3"-isopropoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone

To a solution of 17-ethyl-1,14-dihydroxy-12-2'-(4"-hydroxy-3"-isopropoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19-21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone (88.4 mg in 1.1 mLmethylene chloride) at 0° C. was added α-diazoacetophenone (31.6 mg)followed by boron trifluoride etherat (2.7 μL). After 20 minutes,additional boron trifluoride etherate (3 μL) was added and the mixturewarmed slowly to room temperature. The reaction was quenched after 1.5hours by the addition of saturated sodium bicarbonate solution. Themixture was extracted with ethyl acetate, washed with saturated sodiumchloride solution, and the organic portion dried over magnesium sulfate.Purification by flash chromatography on silica gel (ethyl acetate:hexane(1:2)+1% methanol) followed by silica gel preparative TLC(acetone:hexane 2:8) gave the title compound (2.8 mg).

MS: (FAB) 960 (M+Na) partial ¹ H NMR δ: 7.90 (d, J=7 Hz,, 2H); 7.55 (t,J=7 Hz, 1H); 7.43 (t, J=7 Hz, 2H); 5.30M, 5.16m (brs, 1H); 4.41 (brd,J=14 Hz, 1H); 3.10 (d, J=2.5 Hz, 1H); 1.14 (d, J=6 Hz, 3H); 1.11 (d, J=6Hz, 3H).

EXAMPLES 158-196

Utilizing the general procedures described in Examples 1 to 157, thefollowing compounds of Formula I (wherein R⁴ is hydrogen, R⁵ is methyl,ethyl, propyl or allyl and n is 2) are prepared from the appropriatelysubstituted starting materials and reagents.

    __________________________________________________________________________    EXAMPLE                                                                       NO.   R.sup.1             R.sup.2 R.sup.3                                                                          R.sup.5                                  __________________________________________________________________________    158                                                                                  ##STR18##          CH.sub.3                                                                              H  CH.sub.3 CH.sub.2                        159                                                                                  ##STR19##          CH.sub.2 CHCH.sub.2                                                                   OH CH.sub.3 CH.sub.2                        160                                                                                  ##STR20##          CH.sub.3                                                                              OH CH.sub.2 CHCH.sub.2                      161                                                                                  ##STR21##          CH.sub.3                                                                              OH CH.sub.3 CH.sub.2 CH.sub.2               162                                                                                  ##STR22##          CH.sub.3                                                                              OH CH.sub.3 CH.sub.2                        163                                                                                  ##STR23##          CH.sub.3                                                                              OH CH.sub.3 CH.sub.2                        164                                                                                  ##STR24##          CH.sub.3                                                                              OH CH.sub.3 CH.sub.2 CH.sub.2               165                                                                                  ##STR25##          CH.sub.3                                                                              H  CH.sub.2 CHCH.sub.2                      166                                                                                  ##STR26##          CH.sub.2 CHCH.sub.2                                                                   OH CH.sub.3 CH.sub.2                        167                                                                                  ##STR27##          CH.sub.3                                                                              OH CH.sub.3 CH.sub.2                        168                                                                                  ##STR28##          CH.sub.3                                                                              OH CH.sub.3 CH.sub.2                        169                                                                                  ##STR29##          CH.sub.3                                                                              OH CH.sub.3 CH.sub.2                        170                                                                                  ##STR30##          CH.sub.3                                                                              OH CH.sub.3 CH.sub.2                        171                                                                                  ##STR31##          CH.sub.3                                                                              OH CH.sub.3 CH.sub.2                        172                                                                                  ##STR32##          CH.sub.3                                                                              H  CH.sub.2 CHCH.sub.2                      173                                                                                  ##STR33##          CH.sub.3                                                                              OH CH.sub.3 CH.sub.2                        174                                                                                  ##STR34##          CH.sub.3                                                                              OH CH.sub.3 CH.sub.2                        175                                                                                  ##STR35##          CH.sub.3                                                                              OH CH.sub.3 CH.sub.2                        176                                                                                  ##STR36##          CH.sub.3                                                                              OH CH.sub.3                                 177                                                                                  ##STR37##          CH.sub.3                                                                              OH CH.sub.3 CH.sub.2                        178                                                                                  ##STR38##          CH.sub.3                                                                              OH CH.sub.3 CH.sub.2                        179                                                                                  ##STR39##          CH.sub.3                                                                              OH CH.sub.3 CH.sub.2                        180                                                                                  ##STR40##          CH.sub.3                                                                              H  CH.sub.3 CH.sub.2                        181                                                                                  ##STR41##          CH.sub.3                                                                              H  CH.sub.3 CH.sub.2                        182                                                                                  ##STR42##          CH.sub.3 CH.sub.2                                                                     OH CH.sub.3 CH.sub.2                        183                                                                                  ##STR43##          (CH.sub.3).sub.2 CH                                                                   OH CH.sub.3 CH.sub.2                        184                                                                                  ##STR44##          (CH.sub.3).sub.2 CH                                                                   OH CH.sub.3 CH.sub.2                        185                                                                                  ##STR45##          CH.sub.3 CH.sub.2                                                                     OH CH.sub.3 CH.sub.2                        186                                                                                  ##STR46##          CH.sub.3 CH.sub.2 CH.sub.2                                                            OH CH.sub.3 CH.sub.2                        187                                                                                  ##STR47##          CH.sub.3 CH.sub.2 CH.sub.2                                                            OH CH.sub.3 CH.sub.2                        188                                                                                  ##STR48##          CH.sub.3 CH.sub.2 CH.sub.2                                                            OH CH.sub.3 CH.sub.2                        189                                                                                  ##STR49##          (CH.sub.3).sub.2 CH                                                                   OH CH.sub.3 CH.sub.2                        190                                                                                  ##STR50##          (CH.sub.3).sub.2 CH                                                                   OH CH.sub.3 CH.sub.2                        191   H.sub.2 NCH.sub.2 CH.sub.2                                                                        CH.sub.3                                                                              OH CH.sub.3 CH.sub.2                        192   H.sub.2 NCH.sub.2 CH.sub.2                                                                        CH.sub.3                                                                              H  CH.sub.3 CH.sub.2                        193   (CH.sub.3).sub.2 NCH.sub.2 CH.sub.2                                                               CH.sub.3                                                                              OH CH.sub.3 CH.sub.2                        194   (CH.sub.3).sub.2 NCH.sub.2 CH.sub.2                                                               CH.sub.3                                                                              H  CH.sub.3 CH.sub.2                        195   CH.sub.3 NHCH.sub.2 CH.sub.2                                                                      CH.sub.3                                                                              OH CH.sub.3 CH.sub.2                        196   CH.sub.3 NHCH.sub.2 CH.sub.2                                                                      CH.sub.3                                                                              H  CH.sub.3 CH.sub.2                        __________________________________________________________________________

EXAMPLE 197 T-Cell Proliferation Assay

1. Sample Preparation

The compounds to be assayed were dissolved in absolute ethanol at 1mg/ml.

2. Assay

Spleens from C57B1/6 mice were taken under sterile conditions and gentlydissociated in ice-cold RPMI 1640 culture medium (GIBC), Grand Island,N.Y.) supplemented with 10% heat-inactivated fetal calf serum (GIBO)).Cells were pelleted by centrifugation at 1500 rpm for 8 minutes.Contaminating red cells were removed by treating the pellet withammonium chloride lysing buffer (GIBO)) for 2 minutes at 4° C. Coldmedium was added and cells were again centrifuged at 1500 rpm for 8minutes. T lymphocytes were then isolated by separation of the cellsuspension on nylon wool columns as follows: Nylon wool columns wereprepared by packing approximately 4 grams of washed and dried nylon woolinto 20 ml plastic syringes. The columns were sterilized by autoclavingat 25° F. for 30 minutes. Nylon wool columns were wetted with warm (37°C.) culture medium and rinsed with the same medium. Washed spleen cellsresuspended in warm medium were slowly applied to the nylon wool. Thecolumns were then incubated in an upright position at 37° C. for 1 hour.Non-adherent T lymphocytes were eluted from the columns with warmculture medium and the cell suspensions were spun as above.

Purified T lymphocytes were resuspended at 2.5×10⁵ cells/ml in completeculture medium composed of RPMI 1640 medium with 10% heat-inactivatedfetal calf serum, 100 mM glutamine, 1 mM sodium pyruvate, 2×10-⁵ M2-mercaptoethanol and 50 μg/ml gentamycin. Ionomycin was added at 250ng/ml and PMA at 10 ng/ml. The cell suspension was immediatelydistributed into 96 well flat-bottom microculture plates (Costar) at 200μl/well. The various dilutions of the compound to be tested were thenadded in triplicate wells at 20 μl/well. The compound17-allyl-1,14-dihydroxy-12-2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone was used as a standard.The culture plates were then incubated at 37° C. in a humidifiedatmosphere of 5% CO₂ -95% air for 44 hours. The proliferation of Tlymphocytes was assessed by measurement of tritiated thymidineincorporation. After 44 hours of culturing, the cells werepulse-labelled with 2 μCi/well of tritiated thymidine (NEN, Cambridge,Mass.). After another 4 hours of incubation, cultures were harvested onglass fiber filters using a multiple sample harvester. Radioactivity offilter discs corresponding to individual wells was measured by standardliquid scintillation counting methods (Betacounter). Mean counts perminute of replicate wells were calculated and the results expressed asconcentration of compound required to inhibit tritiated thymidine uptakeof T-cells by 50%.

A selection of compounds were tested according to the previousprocedure. The title compounds of the following Examples had activity ininhibiting the proliferation of T-cells in the aforementioned assay:

1, 2A, 2B, 3, 4, 5, 6A, 6B, 7, 8A, 8B, 9, 10A, 10B, 11, 12A, 12B, 13,14, 15A, 15B, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 43, 44, 45,46A, 46B, 47B, 48A, 49A, 49B, 50A, 50B, 51A, 51B, 52, 53, 54A, 54B, 55,56, 57, 58, 59, 60, 61, 64, 70, 73, 76, 77, 77B, 78, 79, 80, 81, 82, 83,84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100,101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114,115, 116, 117, 118, 119, 120, 121, 122A, 122B, 123A, 123B, 124A, 124B,125, 126A, 126B, 127A, 127B, 128A, 128B, 129A, 129B, 130, 131, 132, 133,134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147,148, 149, 150, 151, 152, 153, 154, 155, 156, & 157.

The results of this assay are representative of the intrinsicimmunosuppressive activity of the compounds of the present invention.

While the foregoing specification teaches the principles of the presentinvention, with examples provided for the purpose of illustration, itwill be understood that the practice of the invention encompasses all ofthe casual variations, adaptations, modifications, deletions, oradditions of procedures and protocols described herein, as come withinthe scope of the following claims and its equivalents.

What is claimed is:
 1. A compound of Formula V, VII, IX, X: ##STR51##wherein: R³ is OH or H;R¹⁵ and R² are selected from the following groupsof substituents:

    ______________________________________                                        R.sup.15             R.sup.2                                                  ______________________________________                                        H                    H                                                        2-F                  H                                                        2-Cl                 H                                                        2-Br                 H                                                        2-CN                 H                                                        2-CH.sub.3           H                                                        2-CF.sub.3           H                                                        2-CH.sub.3 CH.sub.2  H                                                        2-OH                 H                                                        2-NO.sub.2           H                                                        2-NH.sub.2           H                                                        2-CF.sub.3 O         H                                                        2-CH.sub.3 O         H                                                        2-CH.sub.3 CH.sub.2 O                                                                              H                                                        2-CH.sub.3 S         H                                                        2-CH.sub.3 S(O)      H                                                        2-CH.sub.3 SO.sub.2  H                                                        3-F                  H                                                        3-Cl                 H                                                        3-Br                 H                                                        3-CN                 H                                                        3-CH.sub.3           H                                                        3-CF.sub.3           H                                                        3-CH.sub.3 CH.sub.2  H                                                        3-OH                 H                                                        3-NO.sub.2           H                                                        3-NH.sub.2           H                                                        3-CF.sub.3 O         H                                                        3-CH.sub.3 O         H                                                        3-CH.sub.3 CH.sub.2 O                                                                              H                                                        3-CH.sub.3 S         H                                                        3-CH.sub.3 S(O)      H                                                        3-CH.sub.3 SO.sub.2  H                                                        4-F                  H                                                        4-Cl                 H                                                        4-Br                 H                                                        4-CN                 H                                                        4-CH.sub.3           H                                                        4-CF.sub.3           H                                                        4-CH.sub.3 CH.sub.2  H                                                        4-OH                 H                                                        4-NO.sub.2           H                                                        4-NH.sub.2           H                                                        4-CF.sub.3 O         H                                                        4-CH.sub.3 O         H                                                        4-CH.sub.3 CH.sub.2 O                                                                              H                                                        4-CH.sub.3 S         H                                                        4-CH.sub.3 S(O)      H                                                        4-CH.sub.3 SO.sub.2  H                                                        3,5-di-F             H                                                        3,5-di-Cl            H                                                        3,5-di-Br            H                                                        3,5-di-CH.sub.3      H                                                        3,5-di-CH.sub.3 CH.sub.2                                                                           H                                                        3,5-di-CH.sub.3 O    H                                                        3,5-di-CH.sub.3 CH.sub.2 O                                                                         H                                                        H                    CH.sub.3                                                 2-F                  CH.sub.3                                                 2-Cl                 CH.sub.3                                                 2-Br                 CH.sub.3                                                 2-CN                 CH.sub.3                                                 2-CH.sub.3           CH.sub.3                                                 2-CF.sub.3           CH.sub.3                                                 2-CH.sub.3 CH.sub.2  CH.sub.3                                                 2-OH                 CH.sub.3                                                 2-NO.sub.2           CH.sub.3                                                 2-NH.sub.2           CH.sub.3                                                 2-CF.sub.3 O         CH.sub.3                                                 2-CH.sub.3 O         CH.sub.3                                                 2-CH.sub.3 CH.sub.2 O                                                                              CH.sub.3                                                 2-CH.sub.3 S         CH.sub.3                                                 2-CH.sub.3 S(O)      CH.sub.3                                                 2-CH.sub.3 SO.sub.2  CH.sub.3                                                 3-F                  CH.sub.3                                                 3-Cl                 CH.sub.3                                                 3-Br                 CH.sub.3                                                 3-CN                 CH.sub.3                                                 3-CH.sub.3           CH.sub.3                                                 3-CF.sub.3           CH.sub.3                                                 3-CH.sub.3 CH.sub.2  CH.sub.3                                                 3-OH                 CH.sub.3                                                 3-NO.sub.2           CH.sub.3                                                 3-NH.sub.2           CH.sub.3                                                 3-CF.sub.3 O         CH.sub.3                                                 3-CH.sub.3 O         CH.sub.3                                                 3-CH.sub.3 CH.sub.2 O                                                                              CH.sub.3                                                 3-CH.sub.3 S         CH.sub.3                                                 3-CH.sub.3 S(O)      CH.sub.3                                                 3-CH.sub.3 SO.sub.2  CH.sub.3                                                 4-F                  CH.sub.3                                                 4-Cl                 CH.sub.3                                                 4-Br                 CH.sub.3                                                 4-CN                 CH.sub.3                                                 4-CH.sub.3           CH.sub.3                                                 4-CF.sub.3           CH.sub.3                                                 4-CH.sub.3 CH.sub.2  CH.sub.3                                                 4-OH                 CH.sub.3                                                 4-NO.sub.2           CH.sub.3                                                 4-NH.sub.2           CH.sub.3                                                 4-CF.sub.3 O         CH.sub.3                                                 4-CH.sub.3 O         CH.sub.3                                                 4-CH.sub.3 CH.sub.2 O                                                                              CH.sub.3                                                 4-CH.sub.3 S         CH.sub.3                                                 4-CH.sub.3 S(O)      CH.sub.3                                                 4-CH.sub.3 SO.sub.2  CH.sub.3                                                 3,5-di-F             CH.sub.3                                                 3,5-di-Cl            CH.sub.3                                                 3,5-di-Br            CH.sub.3                                                 3,5-di-CH.sub.3      CH.sub.3                                                 3,5-di-CH.sub.3 CH.sub.2                                                                           CH.sub.3                                                 3,5-di-CH.sub.3 O    CH.sub.3                                                 3,5-di-CH.sub.3 CH.sub.2 O                                                                         CH.sub.3                                                 H                    CH.sub.3 CH.sub.2                                        2-F                  CH.sub.3 CH.sub.2                                        2-Cl                 CH.sub.3 CH.sub.2                                        2-Br                 CH.sub.3 CH.sub.2                                        2-CN                 CH.sub.3 CH.sub.2                                        2-CH.sub.3           CH.sub.3 CH.sub.2                                        2-CF.sub.3           CH.sub.3 CH.sub.2                                        2-CH.sub.3 CH.sub.2  CH.sub.3 CH.sub.2                                        2-OH                 CH.sub.3 CH.sub.2                                        2-NO.sub.2           CH.sub.3 CH.sub.2                                        2-NH.sub.2           CH.sub.3 CH.sub.2                                        2-CF.sub.3 O         CH.sub.3 CH.sub.2                                        2-CH.sub.3 O         CH.sub.3 CH.sub.2                                        2-CH.sub.3 CH.sub.2 O                                                                              CH.sub.3 CH.sub.2                                        2-CH.sub.3 S         CH.sub.3 CH.sub.2                                        2-CH.sub.3 S(O)      CH.sub.3 CH.sub.2                                        2-CH.sub.3 SO.sub.2  CH.sub.3 CH.sub.2                                        3-F                  CH.sub.3 CH.sub.2                                        3-Cl                 CH.sub.3 CH.sub.2                                        3-Br                 CH.sub.3 CH.sub.2                                        3-CN                 CH.sub.3 CH.sub.2                                        3-CH.sub.3           CH.sub.3 CH.sub.2                                        3-CF.sub.3           CH.sub.3 CH.sub.2                                        3-CH.sub.3 CH.sub.2  CH.sub.3 CH.sub.2                                        3-OH                 CH.sub.3 CH.sub.2                                        3-NO.sub.2           CH.sub.3 CH.sub.2                                        3-NH.sub.2           CH.sub.3 CH.sub.2                                        3-CF.sub.3 O         CH.sub.3 CH.sub.2                                        3-CH.sub.3 O         CH.sub.3 CH.sub.2                                        3-CH.sub.3 CH.sub.2 O                                                                              CH.sub.3 CH.sub.2                                        3-CH.sub.3 S         CH.sub.3 CH.sub.2                                        3-CH.sub.3 S(O)      CH.sub.3 CH.sub.2                                        3-CH.sub.3 SO.sub.2  CH.sub.3 CH.sub.2                                        4-F                  CH.sub.3 CH.sub.2                                        4-Cl                 CH.sub.3 CH.sub.2                                        4-Br                 CH.sub.3 CH.sub.2                                        4-CN                 CH.sub.3 CH.sub.2                                        4-CH.sub.3           CH.sub.3 CH.sub.2                                        4-CF.sub.3           CH.sub.3 CH.sub.2                                        4-CH.sub.3 CH.sub.2  CH.sub.3 CH.sub.2                                        4-OH                 CH.sub.3 CH.sub.2                                        4-NO.sub.2           CH.sub.3 CH.sub.2                                        4-NH.sub.2           CH.sub.3 CH.sub.2                                        4-CF.sub.3 O         CH.sub.3 CH.sub.2                                        4-CH.sub.3 O         CH.sub.3 CH.sub.2                                        4-CH.sub.3 CH.sub.2 O                                                                              CH.sub.3 CH.sub.2                                        4-CH.sub.3 S         CH.sub.3 CH.sub.2                                        4-CH.sub.3 S(O)      CH.sub.3 CH.sub.2                                        4-CH.sub.3 SO.sub.2  CH.sub.3 CH.sub.2                                        3,5-di-F             CH.sub.3 CH.sub.2                                        3,5-di-Cl            CH.sub.3 CH.sub.2                                        3,5-di-Br            CH.sub.3 CH.sub.2                                        3,5-di-CH.sub.3      CH.sub.3 CH.sub.2                                        3,5-di-CH.sub.3 CH.sub.2                                                                           CH.sub.3 CH.sub.2                                        3,5-di-CH.sub.3 O    CH.sub.3 CH.sub.2                                        3,5-di-CH.sub.3 CH.sub.2 O                                                                         CH.sub.3 CH.sub.2                                        H                    allyl                                                    2-F                  allyl                                                    2-Cl                 allyl                                                    2-Br                 allyl                                                    2-CN                 allyl                                                    2-CH.sub.3           allyl                                                    2-CF.sub.3           allyl                                                    2-CH.sub.3 CH.sub.2  allyl                                                    2-OH                 allyl                                                    2-NO.sub.2           allyl                                                    2-NH.sub.2           allyl                                                    2-CF.sub.3 O         allyl                                                    2-CH.sub.3 O         allyl                                                    2-CH.sub.3 CH.sub.2 O                                                                              allyl                                                    2-CH.sub.3 S         allyl                                                    2-CH.sub.3 S(O)      allyl                                                    2-CH.sub.3 SO.sub.2  allyl                                                    3-F                  allyl                                                    3-Cl                 allyl                                                    3-Br                 allyl                                                    3-CN                 allyl                                                    3-CH.sub.3           allyl                                                    3-CF.sub.3           allyl                                                    3-CH.sub.3 CH.sub.2  allyl                                                    3-OH                 allyl                                                    3-NO.sub.2           allyl                                                    3-NH.sub.2           allyl                                                    3-CF.sub.3 O         allyl                                                    3-CH.sub.3 O         allyl                                                    3-CH.sub.3 CH.sub.2 O                                                                              allyl                                                    3-CH.sub.3 S         allyl                                                    3-CH.sub.3 S(O)      allyl                                                    3-CH.sub.3 SO.sub.2  allyl                                                    4-F                  allyl                                                    4-Cl                 allyl                                                    4-Br                 allyl                                                    4-CN                 allyl                                                    4-CH.sub.3           allyl                                                    4-CF.sub.3           allyl                                                    4-CH.sub.3 CH.sub.2  allyl                                                    4-OH                 allyl                                                    4-NO.sub.2           allyl                                                    4-NH.sub.2           aliyl                                                    4-CF.sub.3 O         allyl                                                    4-CH.sub.3 O         allyl                                                    4-CH.sub.3 CH.sub.2 O                                                                              allyl                                                    4-CH.sub.3 S         allyl                                                    4-CH.sub.3 S(O)      allyl                                                    4-CH.sub.3 SO.sub.2  allyl                                                    3,5-di-F             allyl                                                    3,5-di-Cl            allyl                                                    3,5-di-Br            allyl                                                    3,5-di-CH.sub.3      allyl                                                    3,5-di-CH.sub.3 CH.sub.2                                                                           allyl                                                    3,5-di-CH.sub.3 O    allyl                                                    3,5-di-CH.sub.3 CH.sub.2 O                                                                         allyl                                                    H                    CH.sub.3 CH.sub.2 CH.sub.2                               2-F                  CH.sub.3 CH.sub.2 CH.sub.2                               2-Cl                 CH.sub.3 CH.sub.2 CH.sub.2                               2-Br                 CH.sub.3 CH.sub.2 CH.sub.2                               2-CN                 CH.sub.3 CH.sub.2 CH.sub.2                               2-CH.sub.3           CH.sub.3 CH.sub.2 CH.sub.2                               2-CF.sub.3           CH.sub.3 CH.sub.2 CH.sub.2                               2-CH.sub.3 CH.sub.2  CH.sub.3 CH.sub.2 CH.sub.2                               2-OH                 CH.sub.3 CH.sub.2 CH.sub.2                               2-NO.sub.2           CH.sub.3 CH.sub.2 CH.sub.2                               2-NH.sub.2           CH.sub.3 CH.sub.2 CH.sub.2                               2-CF.sub.3 O         CH.sub.3 CH.sub.2 CH.sub.2                               2-CH.sub.3 O         CH.sub.3 CH.sub.2 CH.sub.2                               2-CH.sub.3 CH.sub.2 O                                                                              CH.sub.3 CH.sub.2 CH.sub.2                               2-CH.sub.3 S         CH.sub.3 CH.sub.2 CH.sub.2                               2-CH.sub.3 S(O)      CH.sub.3 CH.sub.2 CH.sub.2                               2-CH.sub.3 SO.sub.2  CH.sub.3 CH.sub.2 CH.sub.2                               3-F                  CH.sub.3 CH.sub.2 CH.sub.2                               3-Cl                 CH.sub.3 CH.sub.2 CH.sub.2                               3-Br                 CH.sub.3 CH.sub.2 CH.sub.2                               3-CN                 CH.sub.3 CH.sub.2 CH.sub.2                               3-CH.sub.3           CH.sub.3 CH.sub.2 CH.sub.2                               3-CF.sub.3           CH.sub.3 CH.sub.2 CH.sub.2                               3-CH.sub.3 CH.sub.2  CH.sub.3 CH.sub.2 CH.sub.2                               3-OH                 CH.sub.3 CH.sub.2 CH.sub.2                               3-NO.sub.2           CH.sub.3 CH.sub.2 CH.sub.2                               3-NH.sub.2           CH.sub.3 CH.sub.2 CH.sub.2                               3-CH.sub.3 O         CH.sub.3 CH.sub.2 CH.sub.2                               3-CH.sub.3 CH.sub.2 O                                                                              CH.sub.3 CH.sub.2 CH.sub.2                               3-CH.sub.3 S         CH.sub.3 CH.sub.2 CH.sub.2                               3-CH.sub.3 S(O)      CH.sub.3 CH.sub.2 CH.sub.2                               3-CH.sub.3 SO.sub.2  CH.sub.3 CH.sub.2 CH.sub.2                               4-F                  CH.sub.3 CH.sub.2 CH.sub.2                               4-Cl                 CH.sub.3 CH.sub.2 CH.sub.2                               4-Br                 CH.sub.3 CH.sub.2 CH.sub.2                               4-CN                 CH.sub.3 CH.sub.2 CH.sub.2                               4-CH.sub.3           CH.sub.3 CH.sub.2 CH.sub.2                               4-CF.sub.3           CH.sub.3 CH.sub.2 CH.sub.2                               4-CH.sub.3 CH.sub.2  CH.sub.3 CH.sub.2 CH.sub.2                               4-OH                 CH.sub.3 CH.sub.2 CH.sub.2                               4-NO.sub.2           CH.sub.3 CH.sub.2 CH.sub.2                               4-NH.sub.2           CH.sub.3 CH.sub.2 CH.sub.2                               4-CF.sub.3 O         CH.sub.3 CH.sub.2 CH.sub.2                               4-CH.sub.3 O         CH.sub.3 CH.sub.2 CH.sub.2                               4-CH.sub.3 CH.sub.2 O                                                                              CH.sub.3 CH.sub.2 CH.sub.2                               4-CH.sub.3 S         CH.sub.3 CH.sub.2 CH.sub.2                               4-CH.sub.3 S(O)      CH.sub.3 CH.sub.2 CH.sub.2                               4-CH.sub.3 SO.sub.2  CH.sub.3 CH.sub.2 CH.sub.2                               3,5-di-F             CH.sub.3 CH.sub.2 CH.sub.2                               3,5-di-Cl            CH.sub.3 CH.sub.2 CH.sub.2                               3,5-di-Br            CH.sub.3 CH.sub.2 CH.sub.2                               3,5-di-CH.sub.3      CH.sub.3 CH.sub.2 CH.sub.2                               3,5-di-CH.sub.3 CH.sub.2                                                                           CH.sub.3 CH.sub.2 CH.sub.2                               3,5-di-CH.sub.3 O    CH.sub.3 CH.sub.2 CH.sub.2                               3,5-di-CH.sub.3 CH.sub.2 O                                                                         CH.sub.3 CH.sub.2 CH.sub.2                               H                    HOCH.sub.2 CH.sub.2                                      2-F                  HOCH.sub.2 CH.sub.2                                      2-Cl                 HOCH.sub.2 CH.sub.2                                      2-Br                 HOCH.sub.2 CH.sub.2                                      2-CN                 HOCH.sub.2 CH.sub.2                                      2-CH.sub.3           HOCH.sub.2 CH.sub.2                                      2-CF.sub.3           HOCH.sub.2 CH.sub.2                                      2-CH.sub.3 CH.sub.2  HOCH.sub.2 CH.sub.2                                      2-OH                 HOCH.sub.2 CH.sub.2                                      2-NO.sub.2           HOCH.sub.2 CH.sub.2                                      2-NH.sub.2           HOCH.sub.2 CH.sub.2                                      2-CF.sub.3 O         HOCH.sub.2 CH.sub.2                                      2-CH.sub.3 O         HOCH.sub.2 CH.sub.2                                      2-CH.sub.3 CH.sub.2 O                                                                              HOCH.sub.2 CH.sub.2                                      2-CH.sub.3 S         HOCH.sub.2 CH.sub.2                                      2-CH.sub.3 S(O)      HOCH.sub.2 CH.sub.2                                      2-CH.sub.3 SO.sub.2  HOCH.sub.2 CH.sub.2                                      3-F                  HOCH.sub.2 CH.sub.2                                      3-Cl                 HOCH.sub.2 CH.sub.2                                      3-Br                 HOCH.sub.2 CH.sub.2                                      3-CN                 HOCH.sub.2 CH.sub.2                                      3-CH.sub.3           HOCH.sub.2 CH.sub.2                                      3-CF.sub.3           HOCH.sub.2 CH.sub.2                                      3-CH.sub.3 CH.sub.2  HOCH.sub.2 CH.sub.2                                      3-OH                 HOCH.sub.2 CH.sub.2                                      3-NO.sub.2           HOCH.sub.2 CH.sub.2                                      3-NH.sub.2           HOCH.sub.2 CH.sub.2                                      3-CF.sub.3 O         HOCH.sub.2 CH.sub.2                                      3-CH.sub.3 O         HOCH.sub.2 CH.sub.2                                      3-CH.sub.3 CH.sub.2 O                                                                              HOCH.sub.2 CH.sub.2                                      3-CH.sub.3 S         HOCH.sub.2 CH.sub.2                                      3-CH.sub.3 S(O)      HOCH.sub.2 CH.sub.2                                      3-CH.sub.3 SO.sub.2  HOCH.sub.2 CH.sub.2                                      4-F                  HOCH.sub.2 CH.sub.2                                      4-Cl                 HOCH.sub.2 CH.sub.2                                      4-Br                 HOCH.sub.2 CH.sub.2                                      4-CN                 HOCH.sub.2 CH.sub.2                                      4-CH.sub.3           HOCH.sub.2 CH.sub.2                                      4-CF.sub.3           HOCH.sub.2 CH.sub.2                                      4-CH.sub.3 CH.sub.2  HOCH.sub.2 CH.sub.2                                      4-OH                 HOCH.sub.2 CH.sub.2                                      4-NO.sub.2           HOCH.sub.2 CH.sub.2                                      4-NH.sub.2           HOCH.sub.2 CH.sub.2                                      4-CF.sub.3 O         HOCH.sub.2 CH.sub.2                                      4-CH.sub.3 O         HOCH.sub.2 CH.sub.2                                      4-CH.sub.3 CH.sub.2 O                                                                              HOCH.sub.2 CH.sub.2                                      4-CH.sub.3 S         HOCH.sub.2 CH.sub.2                                      4-CH.sub.3 S(O)      HOCH.sub.2 CH.sub.2                                      4-CH.sub.3 SO.sub.2  HOCH.sub.2 CH.sub.2                                      3,5-di-F             HOCH.sub.2 CH.sub.2                                      3,5-di-Cl            HOCH.sub.2 CH.sub.2                                      3,5-di-Br            HOCH.sub.2 CH.sub.2                                      3,5-di-CH.sub.3      HOCH.sub.2 CH.sub.2                                      3,5-di-CH.sub.3 CH.sub.2                                                                           HOCH.sub.2 CH.sub.2                                      3,5-di-CH.sub.3 O    HOCH.sub.2 CH.sub.2                                      3,5-di-CH.sub.3 CH.sub.2 O                                                                         HOCH.sub.2 CH.sub.2                                      H                    (CH.sub.3).sub.2 CH                                      2-F                  (CH.sub.3).sub.2 CH                                      2-Cl                 (CH.sub.3).sub.2 CH                                      2-Br                 (CH.sub.3).sub.2 CH                                      2-CN                 (CH.sub.3).sub.2 CH                                      2-CH.sub.3           (CH.sub.3).sub.2 CH                                      2-CF.sub.3           (CH.sub.3).sub.2 CH                                      2-CH.sub.3 CH.sub.2  (CH.sub.3).sub.2 CH                                      2-OH                 (CH.sub.3).sub.2 CH                                      2-NO.sub.2           (CH.sub.3).sub.2 CH                                      2-NH.sub.2           (CH.sub.3).sub.2 CH                                      2-CF.sub.3 O         (CH.sub.3).sub.2 CH                                      2-CH.sub.3 O         (CH.sub.3).sub.2 CH                                      2-CH.sub.3 CH.sub.2 O                                                                              (CH.sub.3).sub.2 CH                                      2-CH.sub.3 S         (CH.sub.3).sub.2 CH                                      2-CH.sub.3 S(O)      (CH.sub.3).sub.2 CH                                      2-CH.sub.3 SO.sub.2  (CH.sub.3).sub.2 CH                                      3-F                  (CH.sub.3).sub.2 CH                                      3-Cl                 (CH.sub.3).sub.2 CH                                      3-Br                 (CH.sub.3).sub.2 CH                                      3-CN                 (CH.sub.3).sub.2 CH                                      3-CH.sub.3           (CH.sub.3).sub.2 CH                                      3-CF.sub.3           (CH.sub.3).sub.2 CH                                      3-CH.sub.3 CH.sub.2  (CH.sub.3).sub.2 CH                                      3-OH                 (CH.sub.3).sub.2 CH                                      3-NO.sub.2           (CH.sub.3).sub.2 CH                                      3-NH.sub.2           (CH.sub.3).sub.2 CH                                      3-CF.sub.3 O         (CH.sub.3).sub.2 CH                                      3-CH.sub.3 O         (CH.sub.3).sub.2 CH                                      3-CH.sub.3 CH.sub.2 O                                                                              (CH.sub.3).sub.2 CH                                      3-CH.sub.3 S         (CH.sub.3).sub.2 CH                                      3-CH.sub.3 S(O)      (CH.sub.3).sub.2 CH                                      3-CH.sub.3 SO.sub.2  (CH.sub.3).sub.2 CH                                      4-F                  (CH.sub.3).sub.2 CH                                      4-Cl                 (CH.sub.3).sub.2 CH                                      4-Br                 (CH.sub.3).sub.2 CH                                      4-CN                 (CH.sub.3).sub.2 CH                                      4-CH.sub.3           (CH.sub.3).sub.2 CH                                      4-CF.sub.3           (CH.sub.3).sub.2 CH                                      4-CH.sub.3 CH.sub.2  (CH.sub.3).sub.2 CH                                      4-OH                 (CH.sub.3).sub.2 CH                                      4-NO.sub.2           (CH.sub.3).sub.2 CH                                      4-NH.sub.2           (CH.sub.3).sub.2 CH                                      4-CF.sub.3 O         (CH.sub.3).sub.2 CH                                      4-CH.sub.3 O         (CH.sub.3).sub.2 CH                                      4-CH.sub.3 CH.sub.2 O                                                                              (CH.sub.3).sub.2 CH                                      4-CH.sub.3 S         (CH.sub.3).sub.2 CH                                      4-CH.sub.3 S(O)      (CH.sub.3).sub.2 CH                                      4-CH.sub.3 SO.sub.2  (CH.sub.3).sub.2 CH                                      3,5-di-F             (CH.sub.3).sub.2 CH                                      3,5-di-Cl            (CH.sub.3).sub.2 CH                                      3,5-di-Br            (CH.sub.3).sub.2 CH                                      3,5-di-CH.sub.3      (CH.sub.3).sub.2 CH                                      3,5-di-CH.sub.3 CH.sub.2                                                                           (CH.sub.3).sub.2 CH                                      3,5-di-CH.sub.3 O    (CH.sub.3).sub.2 CH                                      3,5-di-CH.sub.3 CH.sub.2 O                                                                         (CH.sub.3).sub.2 CH                                      ______________________________________                                    

R¹⁶ is H, methyl, ethyl, allyl or benzyl; R¹⁷ and R¹⁸ are hydrogen,methyl or ethyl;or a pharmaceutically acceptable salt thereof.
 2. Acompound of Formula VI, VIII: ##STR52## wherein: R³ is OH or H;R¹⁵ andR² are selected from the following groups of substituents:

    ______________________________________                                        R.sup.15             R.sup.2                                                  ______________________________________                                        2-F                  H                                                        2-Cl                 H                                                        2-Br                 H                                                        2-CN                 H                                                        2-CH.sub.3           H                                                        2-CF.sub.3           H                                                        2-CH.sub.3 CH.sub.2  H                                                        2-OH                 H                                                        2-NO.sub.2           H                                                        2-NH.sub.2           H                                                        2-CF.sub.3 O         H                                                        2-CH.sub.3 O         H                                                        2-CH.sub.3 CH.sub.2 O                                                                              H                                                        2-CH.sub.3 S         H                                                        2-CH.sub.3 S(O)      H                                                        2-CH.sub.3 SO.sub.2  H                                                        3-F                  H                                                        3-Cl                 H                                                        3-Br                 H                                                        3-CN                 H                                                        3-CH.sub.3           H                                                        3-CF.sub.3           H                                                        3-CH.sub.3 CH.sub.2  H                                                        3-NO.sub.2           H                                                        3-NH.sub.2           H                                                        3-CF.sub.3 O         H                                                        3-CH.sub.3 CH.sub.2 O                                                                              H                                                        3-CH.sub.3 S         H                                                        3-CH.sub.3 S(O)      H                                                        3-CH.sub.3 SO.sub.2  H                                                        4-F                  H                                                        4-Cl                 H                                                        4-Br                 H                                                        4-CN                 H                                                        4-CH.sub.3           H                                                        4-CF.sub.3           H                                                        4-CH.sub.3 CH.sub.2  H                                                        4-NO.sub.2           H                                                        4-NH.sub.2           H                                                        4-CF.sub.3 O         H                                                        4-CH.sub.3 CH.sub.2 O                                                                              H                                                        4-CH.sub.3 S         H                                                        4-CH.sub.3 S(O)      H                                                        4-CH.sub.3 SO.sub.2  H                                                        3,5-di-Cl            H                                                        3,5-di-Br            H                                                        3,5-di-CH.sub.3      H                                                        3,5-di-CH.sub.3 CH.sub.2                                                                           H                                                        3,5-di-CH.sub.3 CH.sub.2 O                                                                         H                                                        2-F                  CH.sub.3                                                 2-Cl                 CH.sub.3                                                 2-Br                 CH.sub.3                                                 2-CN                 CH.sub.3                                                 2-CH.sub.3           CH.sub.3                                                 2-CF.sub.3           CH.sub.3                                                 2-CH.sub.3 CH.sub.2  CH.sub.3                                                 2-OH                 CH.sub.3                                                 2-NO.sub.2           CH.sub.3                                                 2-NH.sub.2           CH.sub.3                                                 2-CF.sub.3 O         CH.sub.3                                                 2-CH.sub.3 O         CH.sub.3                                                 2-CH.sub.3 CH.sub.2 O                                                                              CH.sub.3                                                 2-CH.sub.3 S         CH.sub.3                                                 2-CH.sub.3 S(O)      CH.sub.3                                                 2-CH.sub.3 SO.sub.2  CH.sub.3                                                 3-F                  CH.sub.3                                                 3-Cl                 CH.sub.3                                                 3-Br                 CH.sub.3                                                 3-CN                 CH.sub.3                                                 3-CF.sub.3           CH.sub.3                                                 3-NO.sub.2           CH.sub.3                                                 3-NH.sub.2           CH.sub.3                                                 3-CF.sub.3 O         CH.sub.3                                                 3-CH.sub.3 CH.sub.2 O                                                                              CH.sub.3                                                 3-CH.sub.3 S         CH.sub.3                                                 3-CH.sub.3 S(O)      CH.sub.3                                                 3-CH.sub.3 SO.sub.2  CH.sub.3                                                 4-F                  CH.sub.3                                                 4-Cl                 CH.sub.3                                                 4-Br                 CH.sub.3                                                 4-CN                 CH.sub.3                                                 4-CF.sub.3           CH.sub.3                                                 4-CH.sub.3 CH.sub.2  CH.sub.3                                                 4-NO.sub.2           CH.sub.3                                                 4-NH.sub.2           CH.sub.3                                                 4-CF.sub.3 O         CH.sub.3                                                 4-CH.sub.3 O         CH.sub.3                                                 4-CH.sub.3 CH.sub.2 O                                                                              CH.sub.3                                                 4-CH.sub.3 S         CH.sub.3                                                 4-CH.sub.3 S(O)      CH.sub.3                                                 4-CH.sub.3 SO.sub.2  CH.sub.3                                                 3,5-di-Cl            CH.sub.3                                                 3,5-di-Br            CH.sub.3                                                 3,5-di-CH.sub.3      CH.sub.3                                                 3,5-di-CH.sub.3 CH.sub.2                                                                           CH.sub.3                                                 3,5-di-CH.sub.3 O    CH.sub.3                                                 3,5-di-CH.sub.3 CH.sub.2 O                                                                         CH.sub.3                                                 H                    CH.sub.3 CH.sub.2                                        2-F                  CH.sub.3 CH.sub.2                                        2-Cl                 CH.sub.3 CH.sub.2                                        2-Br                 CH.sub.3 CH.sub.2                                        2-CN                 CH.sub.3 CH.sub.2                                        2-CH.sub.3           CH.sub.3 CH.sub.2                                        2-CF.sub.3           CH.sub.3 CH.sub.2                                        2-CH.sub.3 CH.sub.2  CH.sub.3 CH.sub.2                                        2-OH                 CH.sub.3 CH.sub.2                                        2-NO.sub.2           CH.sub.3 CH.sub.2                                        2-NH.sub.2           CH.sub.3 CH.sub.2                                        2-CF.sub.3 O         CH.sub.3 CH.sub.2                                        2-CH.sub.3 O         CH.sub.3 CH.sub.2                                        2-CH.sub.3 CH.sub.2 O                                                                              CH.sub.3 CH.sub.2                                        2-CH.sub.3 S         CH.sub.3 CH.sub.2                                        2-CH.sub.3 S(O)      CH.sub.3 CH.sub.2                                        2-CH.sub.3 SO.sub.2  CH.sub.3 CH.sub.2                                        3-F                  CH.sub.3 CH.sub.2                                        3-Cl                 CH.sub.3 CH.sub.2                                        3-Br                 CH.sub.3 CH.sub.2                                        3-CN                 CH.sub.3 CH.sub.2                                        3-CH.sub.3           CH.sub.3 CH.sub.2                                        3-CF.sub.3           CH.sub.3 CH.sub.2                                        3-CH.sub.3 CH.sub.2  CH.sub.3 CH.sub.2                                        3-OH                 CH.sub.3 CH.sub.2                                        3-NO.sub.2           CH.sub.3 CH.sub.2                                        3-NH.sub.2           CH.sub.3 CH.sub.2                                        3-CF.sub.3 O         CH.sub.3 CH.sub.2                                        3-CH.sub.3 O         CH.sub.3 CH.sub.2                                        3-CH.sub.3 CH.sub.2 O                                                                              CH.sub.3 CH.sub.2                                        3-CH.sub.3 S         CH.sub.3 CH.sub.2                                        3-CH.sub.3 S(O)      CH.sub.3 CH.sub.2                                        3-CH.sub.3 SO.sub.2  CH.sub.3 CH.sub.2                                        4-F                  CH.sub.3 CH.sub.2                                        4-Cl                 CH.sub.3 CH.sub.2                                        4-Br                 CH.sub.3 CH.sub.2                                        4-CN                 CH.sub.3 CH.sub.2                                        4-CH.sub.3           CH.sub.3 CH.sub.2                                        4-CF.sub.3           CH.sub.3 CH.sub.2                                        4-CH.sub.3 CH.sub.2  CH.sub.3 CH.sub.2                                        4-OH                 CH.sub.3 CH.sub.2                                        4-NO.sub.2           CH.sub.3 CH.sub.2                                        4-NH.sub.2           CH.sub.3 CH.sub.2                                        4-CF.sub.3 O         CH.sub.3 CH.sub.2                                        4-CH.sub.3 O         CH.sub.3 CH.sub.2                                        4-CH.sub.3 CH.sub.2 O                                                                              CH.sub.3 CH.sub.2                                        4-CH.sub.3 S         CH.sub.3 CH.sub.2                                        4-CH.sub.3 S(O)      CH.sub.3 CH.sub.2                                        4-CH.sub.3 SO.sub.2  CH.sub.3 CH.sub.2                                        3,5-di-F             CH.sub.3 CH.sub.2                                        3,5-di-Cl            CH.sub.3 CH.sub.2                                        3,5-di-Br            CH.sub.3 CH.sub.2                                        3,5-di-CH.sub.3      CH.sub.3 CH.sub.2                                        3,5-di-CH.sub.3 CH.sub.2                                                                           CH.sub.3 CH.sub.2                                        3,5-di-CH.sub.3 O    CH.sub.3 CH.sub.2                                        3,5-di-CH.sub.3 CH.sub.2 O                                                                         CH.sub.3 CH.sub.2                                        H                    allyl                                                    2-F                  allyl                                                    2-Cl                 allyl                                                    2-Br                 allyl                                                    2-CN                 allyl                                                    2-CH.sub.3           allyl                                                    2-CF.sub.3           allyl                                                    2-CH.sub.3 CH.sub.2  allyl                                                    2-OH                 allyl                                                    2-NO.sub.2           allyl                                                    2-NH.sub.2           allyl                                                    2-CF.sub.3 O         allyl                                                    2-CH.sub.3 O         allyl                                                    2-CH.sub.3 CH.sub.2 O                                                                              allyl                                                    2-CH.sub.3 S         allyl                                                    2-CH.sub.3 S(O)      allyl                                                    2-CH.sub.3 SO.sub.2  allyl                                                    3-F                  allyl                                                    3-Cl                 allyl                                                    3-Br                 allyl                                                    3-CN                 allyl                                                    3-CH.sub.3           allyl                                                    3-CF.sub.3           allyl                                                    3-CH.sub.3 CH.sub.2  allyl                                                    3-OH                 allyl                                                    3-NO.sub.2           allyl                                                    3-NH.sub.2           allyl                                                    3-CF.sub.3 O         allyl                                                    3-CH.sub.3 O         allyl                                                    3-CH.sub.3 CH.sub.2 O                                                                              allyl                                                    3-CH.sub.3 S         allyl                                                    3-CH.sub.3 S(O)      allyl                                                    3-CH.sub.3 SO.sub.2  allyl                                                    4-F                  allyl                                                    4-Cl                 allyl                                                    4-Br                 allyl                                                    4-CN                 allyl                                                    4-CH.sub.3           allyl                                                    4-CF.sub.3           allyl                                                    4-CH.sub.3 CH.sub.2  allyl                                                    4-OH                 allyl                                                    4-NO.sub.2           allyl                                                    4-NH.sub.2           allyl                                                    4-CF.sub.3 O         allyl                                                    4-CH.sub.3 O         allyl                                                    4-CH.sub.3 CH.sub.2 O                                                                              allyl                                                    4-CH.sub.3 S         allyl                                                    4-CH.sub.3 S(O)      allyl                                                    4-CH.sub.3 SO.sub.2  allyl                                                    3,5-di-F             allyl                                                    3,5-di-Cl            allyl                                                    3,5-di-Br            allyl                                                    3,5-di-CH.sub.3      allyl                                                    3,5-di-CH.sub.3 CH.sub.2                                                                           allyl                                                    3,5-di-CH.sub.3 O    allyl                                                    3,5-di-CH.sub.3 CH.sub.2 O                                                                         allyl                                                    H                    CH.sub.3 CH.sub.2 CH.sub.2                               2-F                  CH.sub.3 CH.sub.2 CH.sub.2                               2-Cl                 CH.sub.3 CH.sub.2 CH.sub.2                               2-Br                 CH.sub.3 CH.sub.2 CH.sub.2                               2-CN                 CH.sub.3 CH.sub.2 CH.sub.2                               2-CH.sub.3           CH.sub.3 CH.sub.2 CH.sub.2                               2-CF.sub.3           CH.sub.3 CH.sub.2 CH.sub.2                               2-CH.sub.3 CH.sub.2  CH.sub.3 CH.sub.2 CH.sub.2                               2-OH                 CH.sub.3 CH.sub.2 CH.sub.2                               2-NO.sub.2           CH.sub.3 CH.sub.2 CH.sub.2                               2-NH.sub.2           CH.sub.3 CH.sub.2 CH.sub.2                               2-CF.sub.3 O         CH.sub.3 CH.sub.2 CH.sub.2                               2-CH.sub.3 O         CH.sub.3 CH.sub.2 CH.sub.2                               2-CH.sub.3 CH.sub.2 O                                                                              CH.sub.3 CH.sub.2 CH.sub.2                               2-CH.sub.3 S         CH.sub.3 CH.sub.2 CH.sub.2                               2-CH.sub.3 S(O)      CH.sub.3 CH.sub.2 CH.sub.2                               2-CH.sub.3 SO.sub.2  CH.sub.3 CH.sub.2 CH.sub.2                               3-F                  CH.sub.3 CH.sub.2 CH.sub.2                               3-Cl                 CH.sub.3 CH.sub.2 CH.sub.2                               3-Br                 CH.sub.3 CH.sub.2 CH.sub.2                               3-CN                 CH.sub.3 CH.sub.2 CH.sub.2                               3-CH.sub.3           CH.sub.3 CH.sub.2 CH.sub.2                               3-CF.sub.3           CH.sub.3 CH.sub.2 CH.sub.2                               3-CH.sub.3 CH.sub.2  CH.sub.3 CH.sub.2 CH.sub.2                               3-OH                 CH.sub.3 CH.sub.2 CH.sub.2                               3-NO.sub.2           CH.sub.3 CH.sub.2 CH.sub.2                               3-NH.sub.2           CH.sub.3 CH.sub.2 CH.sub.2                               3-CH.sub.3 O         CH.sub.3 CH.sub.2 CH.sub.2                               3-CH.sub.3 CH.sub.2 O                                                                              CH.sub.3 CH.sub.2 CH.sub.2                               3-CH.sub.3 S         CH.sub.3 CH.sub.2 CH.sub.2                               3-CH.sub.3 S(O)      CH.sub.3 CH.sub.2 CH.sub.2                               3-CH.sub.3 SO.sub.2  CH.sub.3 CH.sub.2 CH.sub.2                               4-F                  CH.sub.3 CH.sub.2 CH.sub.2                               4-Cl                 CH.sub.3 CH.sub.2 CH.sub.2                               4-Br                 CH.sub.3 CH.sub.2 CH.sub.2                               4-CN                 CH.sub.3 CH.sub.2 CH.sub.2                               4-CH.sub.3           CH.sub.3 CH.sub.2 CH.sub.2                               4-CF.sub.3           CH.sub.3 CH.sub.2 CH.sub.2                               4-CH.sub.3 CH.sub.2  CH.sub.3 CH.sub.2 CH.sub.2                               4-OH                 CH.sub.3 CH.sub.2 CH.sub.2                               4-NO.sub.2           CH.sub.3 CH.sub.2 CH.sub.2                               4-NH.sub.2           CH.sub.3 CH.sub.2 CH.sub.2                               4-CF.sub.3 O         CH.sub.3 CH.sub.2 CH.sub.2                               4-CH.sub.3 O         CH.sub.3 CH.sub.2 CH.sub.2                               4-CH.sub.3 CH.sub.2 O                                                                              CH.sub.3 CH.sub.2 CH.sub.2                               4-CH.sub.3 S         CH.sub.3 CH.sub.2 CH.sub.2                               4-CH.sub.3 S (O)     CH.sub.3 CH.sub.2 CH.sub.2                               4-CH.sub.3 SO.sub.2  CH.sub.3 CH.sub.2 CH.sub.2                               3,5-di-F             CH.sub.3 CH.sub.2 CH.sub.2                               3,5-di-Cl            CH.sub.3 CH.sub.2 CH.sub.2                               3,5-di-Br            CH.sub.3 CH.sub.2 CH.sub.2                               3,5-di-CH.sub.3      CH.sub.3 CH.sub.2 CH.sub.2                               3,5-di-CH.sub.3 CH.sub.2                                                                           CH.sub.3 CH.sub.2 CH.sub.2                               3,5-di-CH.sub.3 O    CH.sub.3 CH.sub.2 CH.sub.2                               3,5-di-CH.sub.3 CH.sub.2 O                                                                         CH.sub.3 CH.sub.2 CH.sub.2                               H                    HOCH.sub.2 CH.sub.2                                      2-F                  HOCH.sub.2 CH.sub.2                                      2-Cl                 HOCH.sub.2 CH.sub.2                                      2-Br                 HOCH.sub.2 CH.sub.2                                      2-CN                 HOCH.sub.2 CH.sub.2                                      2-CH.sub.3           HOCH.sub.2 CH.sub.2                                      2-CF.sub.3           HOCH.sub.2 CH.sub.2                                      2-CH.sub.3 CH.sub.2  HOCH.sub.2 CH.sub.2                                      2-OH                 HOCH.sub.2 CH.sub.2                                      2-NO.sub.2           HOCH.sub.2 CH.sub.2                                      2-NH.sub.2           HOCH.sub.2 CH.sub.2                                      2-CF.sub.3 O         HOCH.sub.2 CH.sub.2                                      2-CH.sub.3 O         HOCH.sub.2 CH.sub.2                                      2-CH.sub.3 CH.sub.2 O                                                                              HOCH.sub.2 CH.sub.2                                      2-CH.sub.3 S         HOCH.sub.2 CH.sub.2                                      2-CH.sub.3 S(O)      HOCH.sub.2 CH.sub.2                                      2-CH.sub.3 SO.sub.2  HOCH.sub.2 CH.sub.2                                      3-F                  HOCH.sub.2 CH.sub.2                                      3-Cl                 HOCH.sub.2 CH.sub.2                                      3-Br                 HOCH.sub.2 CH.sub.2                                      3-CN                 HOCH.sub.2 CH.sub.2                                      3-CH.sub.3           HOCH.sub.2 CH.sub.2                                      3-CF.sub.3           HOCH.sub.2 CH.sub.2                                      3-CH.sub.3 CH.sub.2  HOCH.sub.2 CH.sub.2                                      3-OH                 HOCH.sub.2 CH.sub.2                                      3-NO.sub.2           HOCH.sub.2 CH.sub.2                                      3-NH.sub.2           HOCH.sub.2 CH.sub.2                                      3-CF.sub.3 O         HOCH.sub.2 CH.sub.2                                      3-CH.sub.3 O         HOCH.sub.2 CH.sub.2                                      3-CH.sub.3 CH.sub.2 O                                                                              HOCH.sub.2 CH.sub.2                                      3-CH.sub.3 S         HOCH.sub.2 CH.sub.2                                      3-CH.sub.3 S(O)      HOCH.sub.2 CH.sub.2                                      3-CH.sub.3 SO.sub.2  HOCH.sub.2 CH.sub.2                                      4-F                  HOCH.sub.2 CH.sub.2                                      4-Cl                 HOCH.sub.2 CH.sub.2                                      4-Br                 HOCH.sub.2 CH.sub.2                                      4-CN                 HOCH.sub.2 CH.sub.2                                      4-CH.sub.3           HOCH.sub.2 CH.sub.2                                      4-CF.sub.3           HOCH.sub.2 CH.sub.2                                      4-CH.sub.3 CH.sub.2  HOCH.sub.2 CH.sub.2                                      4-OH                 HOCH.sub.2 CH.sub.2                                      4-NO.sub.2           HOCH.sub.2 CH.sub.2                                      4-NH.sub.2           HOCH.sub.2 CH.sub.2                                      4-CF.sub.3 O         HOCH.sub.2 CH.sub.2                                      4-CH.sub.3 O         HOCH.sub.2 CH.sub.2                                      4-CH.sub.3 CH.sub.2 O                                                                              HOCH.sub.2 CH.sub.2                                      4-CH.sub.3 S         HOCH.sub.2 CH.sub.2                                      4-CH.sub.3 S(O)      HOCH.sub.2 CH.sub.2                                      4-CH.sub.3 SO.sub.2  HOCH.sub.2 CH.sub.2                                      3,5-di-F             HOCH.sub.2 CH.sub.2                                      3,5-di-Cl            HOCH.sub.2 CH.sub.2                                      3,5-di-Br            HOCH.sub.2 CH.sub.2                                      3,5-di-CH.sub.3      HOCH.sub.2 CH.sub.2                                      3,5-di-CH.sub.3 CH.sub.2                                                                           HOCH.sub.2 CH.sub.2                                      3,5-di-CH.sub.3 O    HOCH.sub.2 CH.sub.2                                      3,5-di-CH.sub.3 CH.sub.2 O                                                                         HOCH.sub.2 CH.sub.2                                      H                    (CH.sub.3).sub.2 CH                                      2-F                  (CH.sub.3).sub.2 CH                                      2-Cl                 (CH.sub.3).sub.2 CH                                      2-Br                 (CH.sub.3).sub.2 CH                                      2-CN                 (CH.sub.3).sub.2 CH                                      2-CH.sub.3           (CH.sub.3).sub.2 CH                                      2-CF.sub.3           (CH.sub.3).sub.2 CH                                      2-CH.sub.3 CH.sub.2  (CH.sub.3).sub.2 CH                                      2-OH                 (CH.sub.3).sub.2 CH                                      2-NO.sub.2           (CH.sub.3).sub.2 CH                                      2-NH.sub.2           (CH.sub.3).sub.2 CH                                      2-CF.sub.3 O         (CH.sub.3).sub.2 CH                                      2-CH.sub.3 O         (CH.sub.3).sub.2 CH                                      2-CH.sub.3 CH.sub.2 O                                                                              (CH.sub.3).sub.2 CH                                      2-CH.sub.3 S         (CH.sub.3).sub.2 CH                                      2-CH.sub.3 S(O)      (CH.sub.3).sub.2 CH                                      2-CH.sub.3 SO.sub.2  (CH.sub.3).sub.2 CH                                      3-F                  (CH.sub.3).sub.2 CH                                      3-Cl                 (CH.sub.3).sub.2 CH                                      3-Br                 (CH.sub.3).sub.2 CH                                      3-CN                 (CH.sub.3).sub.2 CH                                      3-CH.sub.3           (CH.sub.3).sub.2 CH                                      3-CF.sub.3           (CH.sub.3).sub.2 CH                                      3-CH.sub.3 CH.sub.2  (CH.sub.3).sub.2 CH                                      3-OH                 (CH.sub.3).sub.2 CH                                      3-NO.sub.2           (CH.sub.3).sub.2 CH                                      3-NH.sub.2           (CH.sub.3).sub.2 CH                                      3-CF.sub.3 O         (CH.sub.3).sub.2 CH                                      3-CH.sub.3 O         (CH.sub.3).sub.2 CH                                      3-CH.sub.3 CH.sub.2 O                                                                              (CH.sub.3).sub.2 CH                                      3-CH.sub.3 S         (CH.sub.3).sub.2 CH                                      3-CH.sub.3 S(O)      (CH.sub.3).sub.2 CH                                      3-CH.sub.3 SO.sub.2  (CH.sub.3).sub.2 CH                                      4-F                  (CH.sub.3).sub.2 CH                                      4-Cl                 (CH.sub.3).sub.2 CH                                      4-Br                 (CH.sub.3).sub.2 CH                                      4-CN                 (CH.sub.3).sub.2 CH                                      CH.sub.3             (CH.sub.3).sub.2 CH                                      4-CF.sub.3           (CH.sub.3).sub.2 CH                                      CH.sub.3 CH.sub.2    (CH.sub.3).sub.2 CH                                      4-OH                 (CH.sub.3).sub.2 CH                                      4-NO.sub.2           (CH.sub.3).sub.2 CH                                      4-NH.sub.2           (CH.sub.3).sub.2 CH                                      4-CF.sub.3 O         (CH.sub.3).sub.2 CH                                      4-CH.sub.3 O         (CH.sub.3).sub.2 CH                                      4-CH.sub.3 CH.sub.2 O                                                                              (CH.sub.3).sub.2 CH                                      4-CH.sub.3 S         (CH.sub.3).sub.2 CH                                      4-CH.sub.3 S(O)      (CH.sub.3).sub.2 CH                                      4-CH.sub.3 SO.sub.2  (CH.sub.3).sub.2 CH                                      3,5-di-F             (CH.sub.3).sub.2 CH                                      3,5-di-Cl            (CH.sub.3).sub.2 CH                                      3,5-di-Br            (CH.sub.3).sub.2 CH                                      3,5-di-CH.sub.3      (CH.sub.3).sub.2 CH                                      3,5-di-CH.sub.3 CH.sub.2                                                                           (CH.sub.3).sub.2 CH                                      3,5-di-CH.sub.3 O    (CH.sub.3).sub.2 CH                                      3,5-di-CH.sub.3 CH.sub.2 O                                                                         (CH.sub.3).sub.2 CH                                      ______________________________________                                    

R¹⁶ is H, methyl, ethyl, allyl or benzyl;or a pharmaceuticallyacceptable salt thereof.
 3. A compound which is selected from the groupconsisting of:17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-p-t-butylphenyl-2'"-oxoethyl-oxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-m-nitrophenyl-2'"-oxoethyl-oxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-m-isopropoxyphenyl-2'"-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-m-bromophenyl-2'"-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-m-fluorophenyl-2'"-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-m-chloromethylphenyl-2'"-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-m-cyanophenyl-2'"-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-m,m-difluorophenyl-2'"-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-m,m-dimethylphenyl-2'"-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-m-chlorophenyl-2'"-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-m-triflouromethylphenyl-2'"-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-m-fluorophenyl-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-m-chloromethylphenyl-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-m,m-dimethylphenyl-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-m-chlorophenyl-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-m-trifluoromethylphenyl-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-phenyl-2'"-benzyloxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatri-cyclo22.3.1.0.sup.4,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-phenyl-2'"-allyloxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-phenyl-2'"-methoxy-ethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-phenyl-2'"-aminoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramthyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-phenyl-2'"-oxoethyloxy)-3"-allyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-phenyl-2'"-oxoethyloxy)-3"-propyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-phenyl-2'"-oxoethyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(m-fluorophenyl-2'"-oxoethyloxy)-3"-isopropoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"(m-fluorophenyl-2'"-oxoethyloxy)-3"-allyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricycio22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(m-fluorophenyl-2'"-oxoethyloxy)-3"-propyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo2.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(m-fluorophenyl-2'"-oxoethyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(m-methylphenyl-2'"-oxoethyloxy)-3"-isopropoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo2.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(m-methylphenyl-2'"-oxoethyloxy)-3"-allyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(m-methylphenyl-2'"-oxoethyloxy)-3"-propyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo2.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(m-methylphenyl-2'"-oxoethyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(m-methoxyphenyl-2'"-oxoethyloxy)-3"-isopropoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-2.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(m-methoxyphenyl-2'"-oxoethyloxy)-3"-allyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(m-methoxyphenyl-2'"-oxoethyloxy)-3"-propyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoixy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo2.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(m-methoxyphenyl-2'"-oxoethyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1-hydroxy-12-2'-(4"-(2'"-phenyl-2'"-oxoethyloxy)-3"-isopropoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1-hydroxy-12-2'-(4"-(2'"-phenyl-2'"-oxoethyloxy)-3"-allyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1-hydroxy-12-2'-(4"-(2'"-phenyl-2'"-oxoethyloxy)-3"-propyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo 22.3.1.0⁴,9!octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1-hydroxy-12-2'-(4"-(2'"-phenyl-2'"-oxoethyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1-hydroxy-12-2'-(4"-(2'"-(m-fluorophenyl-2'-oxoethyloxy)-3"-isopropoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1-hydroxy-12-2'-(4"-(2'"-(m-fluorophenyl-2'"-oxoethyloxy)-3"-allyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1-hydroxy-12-2'-(4"-(2'"-(m-fluorophenyl-2'"-oxoethyloxy)-3"-propyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1-hydroxy-12-2'-(4"-(2'"-(m-fluorophenyl-2'"-oxoethyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1-hydroxy-12-2'-(4"-(2'"-(m-methylphenyl-2'"-oxoethyloxy)-3"-isopropoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxyo13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo- 22.3.1.0⁴,9!octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1-hydroxy-12-2'-(4"-(2'"-(m-methylphenyl-2'"-oxoethyloxy)-3"-allyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1-hydroxy-12-2'-(4"-(2'"-(m-methylphenyl-2'"-oxoethyloxy)-3"-propyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1-hydroxy-12-2'-(4"-(2'"-(m-methylphenyl-2'"-oxoethyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1-hydroxy-12-2'-(4"-(2'"-(m-methoxyphenyl-2'"-oxoethyloxy)-3"-isopropoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1-hydroxy-12-2'-(4"-(2'"-(m-methoxyphenyl-2'"-oxoethyloxy)-3"-allyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1-hydroxy-12-2'-(4"-(2'"-(m-methoxyphenyl-2'"-oxoethyloxy)-3"-propyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1-hydroxy-12-2'-(4"-(2'"-(m-methoxyphenyl-2'"-oxoethyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1-hydroxy-12-2'-(4"-(2'"-(3"",5""-dimethoxyphenyl-2'"-oxoethyloxy)-3"-isopropoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10, 16-tetraone; 17-ethyl-1-hydroxy-12-2'-(4"-(2'"-(3"",5""-dimethoxyphenyl-2'"-oxoethyloxy)-3"-allyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1-hydroxy-12-2'-(4"-(2'"-(3"",5""-dimethoxyphenyl-2'"-oxoethyloxy)-3"-propyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1-hydroxy-12-2'-(4"-(2'"-(3"",5""-dimethoxyphenyl-2'"-oxoethyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1-hydroxy-12-2'-(4"-(2'"-(3"",5""-dimethoxyphenyl-2'"-hydroxyethyloxy)-3"-isopropoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1-hydroxy-12-2'-(4"-(2'"-(3"",5""-dimethoxyphenyl-2'"-hydroxyethyloxy)-3"-allyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1-hydroxy-12-2'-(4"-(2'"-(3"",5""-dimethoxyphenyl-2'"-hydroxyethyloxy)-3"-propyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1-hydroxy-12-2'-(4"-(2'"-(3"",5""-dimethoxyphenyl-2'"-hydroxyethyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12- 2'-(4"-(2'"-(3"",5""-dimethoxyphenyl-2'"-oxoethyloxy)-3"-isopropoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3"",5""-dimethoxyphenyl-2'"-oxoethyloxy)-3"-allyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3"",5""-dimethoxyphenyl-2""-oxoethyloxy)-3"-propyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3"",5""-dimethoxyphenyl-2'"-oxoethyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos -18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3"",5"-dimethoxyphenyl-2'"-hydroxyethyloxy)-3"-isopropoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3"",5""-dimethoxyphenyl-2'"-hydroxyethyloxy)-3"-allyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12- 2'-(4"-(2'"-(3"",5""-dimethoxyphenyl-2'"-hydroxyethyloxy)-3"-propyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3"",5""-dimethoxyphenyl-2'"-hydroxyethyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1-hydroxy-12-2'-(4"-(2'"-(3"",5""-dimethylphenyl-2'"-oxoethyloxy)-3"-isopropoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1-hydroxy-12-2'-(4"-(2'"(3"",5""-dimethylphenyl-2'"-oxoethyloxy)-3"-allyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1-hydroxy-12-2'-(4"-(2'"-(3"",5""-dimethylphenyl-2'"-oxoethyloxy)-3"-propyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1-hydroxy-12-2'-(4"-(2'"-(3"",5""-dimethylphenyl-2'"-oxoethyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-3,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1-hydroxy -12-2'-(4"-(2'"-(3"",5""-dimethylphenyl-2'"-hydroxyethyloxy)-3"-isopropoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1-hydroxy-12-2'-(4"-(2'"-(3"",5""-dimethylphenyl-2'"-hydroxyethyloxy)-3"-allyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1-hydroxy-12-2'-(4"-(2'"-(3"",5""-dimethylphenyl-2'"-hydroxyethyloxy)-3"-propyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1-hydroxy-12-2'-(4"-(2'"-(3"",5""-dimethylphenyl-2'"-hydroxyethyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3"",5""-dimethylphenyl-2'"-oxoethyloxy)-3"-isopropoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3"",5""-dimethylphenyl-2'"-oxoethyloxy)-3"-allyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3"",5""-dimethylphenyl-2'"-oxoethyloxy)-3"-propyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3"",5""-dimethylphenyl-2'"-oxoethyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3"",5""-dimethylphenyl-2'"-hydroxyethyloxy)-3"-isopropoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3"",5""-dimethylphenyl-2'"-hydroxyethyloxy)-3"-allyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3"",5""-dimethylphenyl-2'"-hydroxyethyloxy)-3"-propyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3"",5""-dimethylphenyl-2'"-hydroxyethyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-phenyl-2'"-hydroxyethyloxy)-3"-isopropoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-phenyl-2'"-hydroxyethyloxy)-3"-allyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-phenyl-2'"-hydroxyethyloxy)-3"-propyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18oene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-phenyl-2'"-hydroxyethyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(m-fluorophenyl-2'"-hydroxyethyloxy)-3"-isopropoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(m-fluorophenyl-2'"-hydroxyethyloxy)-3"-allyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(m-fluorophenyl-2'"-hydroxyethyloxy)-3"-propyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(m-fluorophenyl-2'"-hydroxyethyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(m-methylphenyl-2'"-hydroxyethyloxy)-3"-isopropoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(m-methylphenyl-2'"-hydroxyethyloxy)-3"-allyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(m-methylphenyl-2'"-hydroxyethyloxy)-3"-propyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(m-methylphenyl-2'"-hydroxyethyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(m-methoxyphenyl-2'"-hydroxyethyloxy)-3"-isopropoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(m-methoxyphenyl-2'"-hydroxyethyloxy)-3"-allyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(m-methoxyphenyl-2'"-hydroxyethyloxy)-3"-propyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0.sup.4,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(m-methoxyphenyl-2'"-hydroxyethyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1-hydroxy-12-2'-(4"-(2'"-phenyl-2'"-hydroxyethyloxy)-3"-isopropoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1-hydroxy-12-2'-(4"-(2'"-phenyl-2'"-hydroxyethyloxy)-3"-allyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1-hydroxy-12-2'-(4"-(2'"-phenyl-2'"-hydroxyethyloxy)-3"-propyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1-hydroxy-12-2'-(4"-(2'"-phenyl-2'"-hydroxyethyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1-hydroxy-12-2'-(4"-(2'"-(m-fluorophenyl-2'"-hydroxyethyloxy)-3"-isopropoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1-hydroxy-12-2'-(4"-(2'"-(m-fluorophenyl-2'"-hydroxyethyloxy)-3"-allyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1-hydroxy-12-2'-(4"-(2'"-(m-fluorophenyl-2'"-hydroxyethyloxy)-3"-propyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1-hydroxy-12-2'-(4"-(2'"-(m-fluorophenyl-2'"-hydroxyethyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1-hydroxy-12-2'-(4"-(2'"-(m-methylphenyl-2'"-hydroxyethyloxy)-3"-isopropoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1-hydroxy-12-2'-(4"-(2'"-(m-methylphenyl-2'"-hydroxyethyloxy)-3"-allyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1-hydroxy-12-2'-(4"-(2'"-(m-methylphenyl-2'"-hydroxyethyloxy)-3"-propyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1-hydroxy-12-2'-(4"-(2'"-(m-methylphenyl-2'"-hydroxyethyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1-hydroxy-12-2'-(4"-(2'"-(m-methoxyphenyl-2'"-hydroxyethyloxy)-3"-isopropoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1-hydroxy-12-2'-(4"-(2'"-(m-methoxyphenyl-2'"-hydroxyethyloxy)-3"-allyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1-hydroxy-12-2'-(4"-(2'"-(m-methoxyphenyl-2'"-hydroxyethyloxy)-3"-propyloxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone; 17-ethyl-1-hydroxy-12-2'-(4"-(2'"-(m-methoxyphenyl-2'"-hydroxyethyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-m,m-dichlorophenyl-2'"-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-m,m-dichlorophenyl-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-m,m-bistrifluoromethoxyphenyl-2'"-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-m,m-bistrifluoromethoxy-phenyl-2''-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-m,m-bistrifluoromethylphenyl-2'"-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-m,m-bistrifluoromethylphenyl-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10, 16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-m,m-dihydroxyphenyl-2'"-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-m,m-dihydroxyphenyl-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3"",4"",5""-trimethyl)phenyl-2""-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12- 2'-(4"-(2'"-(3"",4"",5""-trimethyl)phenyl-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3"",5""-dimethyl-4""-methoxy)phenyl-2'"-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3"",5""-dimethyl-4""-methoxy)phenyl-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3"",5""-dimethoxy-4""-methyl)phenyl-2'"-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3"",5""-dimethoxy-4""-methyl)phenyl-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3"",5""-difluoro-4""-methyl)phenyl-2'"-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3"",5""-difluoro-4""-methyl)phenyl-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3"",5""-dimethyl-4""-fluoro)phenyl-2'"-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3"",5""-dimethyl-4-fluoro)phenyl-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3"",5""-dichloro-4""-methyl)phenyl-2'"-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3"",5""-dichloro-4""-methyl)phenyl-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3"",5""-dimethyl-4-chloro)phenyl-2'"-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3"",5""-dimethyl-4""-chloro)phenyl-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3"",5""-bistrifluoromethoxy-4""-methyl)phenyl-2'"-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3"",5""-bistrifluoromethoxy-4""-methyl)phenyl-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0.sup.4,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3"",5""-dimethyl-4""-trifluoromethoxy)phenyl-2'"-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3"",5""-dimethyl-4""-trifluoromethoxy)phenyl-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3"",5""-dimethyl-4""-hydroxy)phenyl-2'"-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3"",5""-dimethyl-4""-hydroxy)phenyl-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3"",5""-methyl)phenyl-2'"-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3"",5""-dihydroxy-4""-methyl)phenyl-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-m-thiomethylphenyl-2'"-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-m-thiomethylphenyl-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-m,m-bis(thiomethyl)phenyl-2'"-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-m,m-bis(thiomethyl)phenyl-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3"",5""-bis(thiomethyl)-4""-methyl)phenyl-2'"-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3"",5""-bis(thiomethyl)-4""-methyl)phenyl-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3""-chloro-5""-methyl)phenyl-2'"-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3""-chloro-5""-methyl)phenyl-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3""-chloro-5""-fluoro)phenyl-2'"-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.04⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3""-chloro-5""-fluoro)phenyl-2""-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3""-chloro-5""-methoxy)phenyl-2'"-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3""-chloro-5""-methoxy)phenyl-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3""-chloro-5""-trifluoromethyl)phenyl-2'"-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3""-chloro-5""-trifluoromethyl)phenyl-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3""-chloro-5""-trifluoromethoxy)phenyl-2'"-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4''-(2'"-(3""-chloro-5""-trifluoromethhoxy)phenyl-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3""-fluoro-5""-methyl)phenyl-2'"-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3""-fluoro-5""-methyl)phenyl-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3""-fluoro-5""-methoxy)phenyl-2'"-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3""-fluoro-5""-methoxy)phenyl-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3""-fluoro-5""-trifluoromethyl)phenyl-2'"-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3""-fluoro-5""-trifluoromethyl)phenyl-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3""-fluoro-5""-trifluoromethoxy)phenyl-2'"-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3""-fluoro-5""-trifluoromethoxy)phenyl-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3""-methyl-5""-methoxy)phenyl-2'"-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3""-methyl-5""-methoxy)phenyl-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3""-methyl-5""-trifluoromethyl)phenyl-2'"-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene -2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(4"-(2'"-(3""-methyl-5""-trifluoromethyl)phenyl-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(3",4"-di-(2'"-phenyl-2'"-oxo-ethyloxy)cyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;17-ethyl-1,14-dihydroxy-12-2'-(3",4"-di-(2'"-phenyl-2'"-hydroxyethyloxy)-cyclohexyl)-1'-methylvinyl!-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo22.3.1.0⁴,9 !octacos-18-ene-2,3,10,16-tetraone;or a pharmaceuticallyacceptable salt thereof.
 4. A pharmaceutical composition comprising apharmaceutical carrier and a therapeutically effective amount of thecompound of claim
 1. 5. A pharmaceutical composition comprising apharmaceutical carrier and a therapeutically effective amount of thecompound of claim
 2. 6. A method for the prevention or treatment ofimmunoregulatroy disorders or diseases comprising the administration ofthe compound of claim
 1. 7. A method for the prevention or treatment ofimmunoregulatory disorders or diseases comprising the administration ofthe compound of claim
 1. 8. A pharmaceutical composition comprising apharmaceutical carrier and a therapeutically effective amount of acompound of claim
 2. 9. A method for the prevention or treatment ofimmunoregulatory disorders or diseases which comprises theadministration of a compound of claim 2.